Consumer medicine information

Intelence Tablets

Etravirine

BRAND INFORMATION

Brand name

Intelence

Active ingredient

Etravirine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Intelence Tablets.

What is in this leaflet

This leaflet answers some common questions about INTELENCE tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given INTELENCE against the benefits this medicine is expected to have for you.

If you have any concerns about being given INTELENCE ask your doctor.

Keep this leaflet while you are taking INTELENCE. You may need to read it again.

What INTELENCE is used for

INTELENCE is a medicine used for the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). INTELENCE works by reducing the amount of HIV in your body. This will improve your immune system and reduce the risk of developing illnesses linked to HIV infection.

INTELENCE is used to treat adults who are infected by HIV and who have used other anti-HIV medicines before. INTELENCE can be used by patients infected with HIV that is resistant to other NNRTIs.

INTELENCE must be taken in combination with other anti-HIV medicines. Your doctor will discuss with you which combination of medicines is best for you.

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

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

Before you take INTELENCE

When you must not use it:

Do not take INTELENCE:

  • if you are allergic (hypersensitive) to etravirine, or other ingredients of INTELENCE. See Product Description at the end of this leaflet for a list of ingredients.

Do not take INTELENCE:

  • if the packaging is torn or shows signs of tampering.
  • if the expiry date (month and year) printed on the pack has passed. If you take INTELENCE after the expiry date it may not work.

Do not combine INTELENCE with any of the following medicines:

  • carbamazepine, phenobarbital, phenytoin (to prevent seizures)
  • rifampicin and rifapentine (to treat some infections such as tuberculosis)
  • products that contain St John's wort (Hypericum perforatum) (a herbal product used for depression)
  • elbasvir/grazoprevir (to treat Hepatitis C)

If you are taking any of these, ask your doctor for advice.

There are other medicines that you need to be careful of when taking INTELENCE (see Taking other medicines).

Before you start to use it:

Take special care with INTELENCE:
INTELENCE is not a cure for HIV infection. It is part of a treatment reducing the amount of virus in the blood.

INTELENCE does not reduce the risk of passing HIV to others through sexual contact or blood contamination. Therefore, you must continue to use appropriate precautions (a condom or other barrier method) to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood.

People taking INTELENCE may still develop infections or other illnesses associated with HIV infection. You must keep in regular contact with your doctor and to monitor your health while taking INTELENCE.

INTELENCE is not for use in children or adolescents, because it has not been sufficiently studied in patients under 18 years of age. INTELENCE has only been used in a limited number of patients aged 65 years or older. If you belong to this age group, discuss the use of INTELENCE with your doctor.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • Problems with your liver.
    Including hepatitis B and/or C. Your doctor may need to evaluate how severe your liver disease is before deciding if you can take INTELENCE.
  • Symptoms of infection.
    In some patients with advanced HIV infection and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response. This improvement enables the body to fight infections that may have been present prior to taking INTELENCE, with no obvious symptoms.
  • Changes in body shape or fat.
    Redistribution, accumulation or loss of body fat may occur in patients receiving a combination of antiretroviral medicines.
  • Rash.
    If a rash occurs, it usually appears soon after anti-HIV treatment is started and often disappears within 1 to 2 weeks, even with continued use of the medication. Occasionally a rash can be severe or potentially life-threatening.
    Contact your doctor immediately if you get a rash.
    Your doctor will advise you how to deal with your symptoms or whether INTELENCE must be stopped.

Tell your doctor immediately if you are pregnant or breast-feeding, or intend to become pregnant or breast-feed. HIV infected mothers must not breast-feed, as there is a possibility of infecting the baby with HIV

During pregnancy and breast-feeding you should not take INTELENCE, unless it is specifically approved by your doctor.

If you have not told your doctor about any of the above, tell them before you start treatment with INTELENCE.

Taking other medicines:

INTELENCE might interact with other medicines. Tell your doctor if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

INTELENCE can be combined with most other anti-HIV medicines belonging to another class. However, some combinations are not recommended. In other cases, increased monitoring and/or a change in the dose of the medicine may be needed.

Therefore, always tell your doctor which other anti-HIV medicines you take. Carefully follow your doctor's instructions, on which medicines can be combined.

Also, tell your doctor or pharmacist if you are taking any of the following:

  • amiodarone, bepridil, digoxin, disopyramide, flecainide, lignocaine, mexiletine, propafenone or quinidine (to treat certain heart disorders, e.g. abnormal heart beat).
  • warfarin (a medicine used to reduce clotting of the blood). Your doctor will have to check your blood.
  • fluconazole, itraconazole, ketoconazole, posaconazole, or voriconazole (to treat fungal infections).
  • clarithromycin (an antibiotic).
  • artemether/lumefantrine (a medicine to treat malaria).
  • rifabutin (a medicine used to treat some infections such as tuberculosis).
  • boceprevir or daclatasvir (to treat Hepatitis C).
  • diazepam (to treat trouble with sleeping and/or anxiety).
  • dexamethasone (a corticosteroid used in a variety of conditions such as inflammation and allergic reactions).
  • atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, or simvastatin (cholesterol-lowering medicines).
  • cyclosporine, sirolimus, or tacrolimus (immunosuppressants).
  • sildenafil, vardenafil, or tadalafil (to treat erectile dysfunction).
  • clopidogrel (a medicine to prevent blood clots)

Taking INTELENCE

How much INTELENCE to take:

Always take INTELENCE exactly as your doctor has told you. You must check with your doctor if you are not sure.

The usual dose of INTELENCE is 200 mg twice daily.

If you are taking INTELENCE 100 mg tablets:
In the morning, take two 100 milligram INTELENCE tablets, following a meal.
In the evening, take two 100 milligram INTELENCE tablets, following a meal.

If you are taking INTELENCE 200 mg tablets:
In the morning, take one 200 milligram INTELENCE tablet, following a meal.
In the evening, take one 200 milligram INTELENCE tablet, following a meal.

Instructions:

  • It is important that you take INTELENCE following a meal. If you take INTELENCE on an empty stomach, only half the amount of INTELENCE is absorbed. Follow your doctor's advice on the type of meal you should be taking with INTELENCE.
  • Swallow the tablets whole with a glass of liquid such as water. Do not chew the tablets.
  • It is possible the tablet may crumble in your mouth; in this case ensure all pieces are swallowed. This does not indicate a problem with the quality of the tablet.
  • If you are unable to swallow the INTELENCE tablet(s) whole, you may do the following:
    - place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough water to cover the medication,
    - stir well for about 1 minute until the water looks milky,
    - if desired, add up to 30 mL (2 tablespoons) more of water or alternatively orange juice or milk (do not place the tablets in orange juice or milk without first adding water),
    - drink it immediately.
    - rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure you take the entire dose.

If you mix INTELENCE tablet(s) with water, take this first, before other liquid anti-HIV medicines that you need to take at the same time.

Contact your doctor if you are not able to swallow the entire dose when mixed with water.

Do not use warm (> 40°C) or carbonated beverages when taking INTELENCE tablet(s).

Make sure that you always have enough INTELENCE available so that you don't run out. For example in case you cannot return home, need to travel or stay in a hospital.

Removing the child resistant cap

The plastic bottle comes with a child resistant cap and should be opened as follows:

  • Push the plastic screw cap down while turning it counter clockwise.
  • Remove the unscrewed cap.

What do I do if I forget to take INTELENCE?

If you notice within 6 hours, you must take the tablets immediately. Always take the tablets following a meal. If you notice after 6 hours, then skip the dose and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

What do I do if I take too much? (overdose):

If you think you or anybody else has taken too much INTELENCE, contact your doctor, pharmacist or the Poisons Information Centre who will advise you what to do.

You can contact the Poisons Information Centre by dialling:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766.

While you are taking INTELENCE

Things you must do:

Do not stop taking INTELENCE without talking to your doctor first HIV therapy may increase your sense of well being. Even if you feel better, do not stop taking INTELENCE or your other anti-HIV medicines. Doing so could increase the risk of the virus developing resistance. Talk to your doctor first.

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor will want to do some blood, urine and other tests from time to time to check on your progress.

Be sure to follow up your doctor's instructions about other medicines you should take, and other things you should do.

Ask your doctor or pharmacist if you have any questions.

Tell any other doctors and pharmacists who are treating you that you are taking INTELENCE. If you are undergoing anaesthesia, tell your anaesthetist that you are taking INTELENCE.

If you are about to be started on any new medicines, tell your doctor or pharmacist that you are taking INTELENCE.

If you become pregnant while taking INTELENCE, tell your doctor immediately.

If you have any further questions on the use of this product, ask your doctor.

Things to be careful of

Driving and using machines
No studies on the effects of INTELENCE on the ability to drive and use machines have been performed. However, you should take into account the possible side effects of INTELENCE before considering driving or using machines.

Side Effects

Like all medicines, INTELENCE can have side effects. Some of these effects may be serious.

Tell your doctor or pharmacist if you do not feel well while you are being treated with INTELENCE.

When treating HIV infection, it is not always easy to identify what side effects are caused by INTELENCE, which are caused by other medicines you are taking, or which are caused by the HIV infection itself.

The most common side effects are:

  • skin rash. The rash is usually mild to moderate. In rare instances, rash can be potentially life-threatening. It is therefore important to contact your doctor immediately if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether INTELENCE must be stopped.
  • diarrhoea, nausea, abdominal pain, vomiting, heartburn, gas, inflammation of the stomach.
  • fatigue, tingling or pain in hands or feet, numbness, headache, sleeplessness, anxiety.
  • kidney failure, high blood pressure, heart attack, diabetes.
  • night sweats.
  • changes in some values of your blood cells or chemistry. These can be seen in the results from blood tests. Your doctor will explain these to you. Examples are: low red blood cell count, low blood platelet count, high or abnormal blood fat levels, high cholesterol levels, high sugar levels.

Other side effects of INTELENCE, which can be serious, include muscle pain, tenderness or weakness.

Some side effects are typical for combination anti-HIV therapy. These are:

  • change in body shape due to fat redistribution. This may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (buffalo hump). The cause and long-term health effects of these conditions are not known at this time.
  • immune reconstitution syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Autoimmune disorders may occur many months after the start of treatment.

If you experience any of these side effects and they worry you, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Tell your doctor if you notice signs or symptoms of infections, such as a fever or rashes. Some people with HIV who have had infections in the past may experience a return of symptoms soon after taking anti-HIV medicines.

Other side effects not listed above may also occur in some people.

Product Description

Storage

INTELENCE tablets should be kept out of reach of children, in a location where the temperature stays below 30°C.

INTELENCE tablets should be stored in the original bottle. Keep the bottle tightly closed in order to protect from moisture. The bottle contains 3 little pouches (desiccants) to keep the tablets dry. These pouches should stay in the bottle all the time and are not to be eaten.

What it looks like:

INTELENCE 100 mg tablets are white to off-white, oval tablet, with "T125" on one side and "100" on the other side. Each plastic bottle contains 120 tablets. The 100 mg tablets are no longer marketed.

INTELENCE 200 mg tablets are white to off-white, biconvex, oblong tablet, with "T200" on one side. Each plastic bottle contains 60 tablets.

Ingredients

What INTELENCE 100 mg tablets contain
The active substance is etravirine. Each 100 mg tablet of INTELENCE contains 100 mg of etravirine.
The other ingredients are hypromellose, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, magnesium stearate and lactose monohydrate.

What INTELENCE 200 mg tablets contain
The active substance is etravirine. Each 200 mg tablet of INTELENCE contains 200 mg of etravirine.
The other ingredients are hypromellose, microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium and magnesium stearate.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Rd
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland, New Zealand
Telephone: 0800 800 806

Registration number

100 mg Tablet: AUST R 145797 (not marketed)

200 mg Tablet AUST R 176557

This leaflet was prepared in: March 2023

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Intelence

Active ingredient

Etravirine

Schedule

S4

 

1 Name of Medicine

Etravirine.

2 Qualitative and Quantitative Composition

Intelence etravirine is available as 100 mg and 200 mg tablets.
Each tablet contains 100 mg or 200 mg of etravirine.

Excipient(s) with known effect.

The 100 mg tablets contain 160 mg of lactose monohydrate.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.

Intelence 100 mg tablet.

White to off-white, oval tablet, debossed with "T125" on one side and "100" on the other side.

Intelence 200 mg tablet.

White to off-white, biconvex, oblong tablet, debossed with "T200" on one side.
Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).
Intelence (etravirine) is a substituted diarylpyrimidine (DAPY) derivative, with potent in vitro activity against wild type HIV-1 as well as NNRTI resistant HIV-1.

4 Clinical Particulars

4.1 Therapeutic Indications

Etravirine, in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in antiretroviral treatment experienced adults who have evidence of viral replication and resistance to non-nucleoside transcriptase inhibitors and other antiretroviral agents.
This indication is based on 24 week analyses from 2 randomised, double blind, placebo controlled trials of etravirine. Both studies were conducted in clinically advanced, 3 class antiretroviral (NNRTI, N(t)RTI, PI) treatment experienced adults (See Section 5.1 Pharmacodynamic Properties, Clinical trials).
Treatment history of patients and genotypic testing should be performed to guide the use of etravirine.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Intelence must always be given in combination with other antiretroviral medicinal products.

Adults.

The recommended oral dose of Intelence is 200 mg (one 200 mg tablet or two 100 mg tablets) taken orally twice daily (b.i.d.), following a meal (see Section 5.2 Pharmacokinetic Properties). Patients should be instructed to swallow the tablet(s) as a whole with a liquid such as water. Patients who are unable to swallow the Intelence tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:
place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough water to cover the medication;
stir well for about 1 minute until the water looks milky;
if desired, add up to 30 mL (2 tablespoons) more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water);
drink it immediately;
rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose.
The use of warm (> 40°C) or carbonated beverages should be avoided.
It is recommended that Intelence tablet(s) dispersed in water be taken before other antiretroviral liquids that may need to be taken concomitantly.

Hepatic impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). The pharmacokinetics of Intelence have not been studied in patients with severe hepatic impairment (Child-Pugh score C) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dose adjustment is required in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Children (less than 12 years of age) and adolescents (12 to 17 years of age).

Treatment with Intelence is not recommended in children and adolescents. The safety and efficacy of Intelence in these populations are under investigation (see Section 5.2 Pharmacokinetic Properties).

Elderly.

Limited information is available in this population (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Pregnancy.

Intelence should be used during pregnancy only if the potential benefit justifies the potential risk. Based on limited data available, no dose adjustment is required during pregnancy and postpartum. (see Section 5.2 Pharmacokinetic Properties, Pregnancy and postpartum; Section 4.6 Fertility, Pregnancy and Lactation; Section 4.2 Dose and Method of Administration, Pregnancy).

Missed dose.

If the patient misses a dose of Intelence within 6 hours of the time it is usually taken, the patient should be told to take Intelence following a meal as soon as possible, and then take the next dose of Intelence at the regularly scheduled time. If a patient misses a dose of Intelence by more than 6 hours of the time it is usually taken, the patient should be told not to take the missed dose and simply resume the usual dosing schedule.

4.3 Contraindications

Hypersensitivity to etravirine or to any of the excipients.

4.4 Special Warnings and Precautions for Use

The use of other active antiretroviral agents with etravirine is associated with an increased likelihood of treatment response.
In patients who have experienced virological failure on an NNRTI and nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) containing regimen, etravirine should not be used in combination with N(t)RTIs only.

Transmission of HIV.

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions to prevent the transmission of HIV should continue to be employed.
The risks and benefits of etravirine have not been established in treatment of naïve patients.

Severe skin rash and hypersensitivity reactions.

Severe, potentially life threatening and fatal skin reactions have been reported with Intelence; Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely (< 0.1%) reported. Hypersensitivity reactions, including DRESS (drug rash with eosinophilia and systemic symptoms), have also been reported and were characterized by rash, constitutional findings and infrequently organ dysfunction, including hepatic failure (see Section 4.8 Adverse Effects (Undesirable Effects)).
In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving Intelence compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1 infected subjects receiving Intelence discontinued from Phase 3 trials due to rash.
Discontinue Intelence immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping Intelence treatment after the onset of severe rash may result in life threatening reaction.

Rash.

Rash has been reported with Intelence. Most frequently, rash was mild to moderate, occurred in the second week of therapy and was infrequent after week 4. Rash was mostly self limiting and generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in females (see Section 4.8 Adverse Effects (Undesirable Effects)).

Fat redistribution.

Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesized. A higher risk of lipodystrophy has been associated with individual factors such as older age and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution (see Section 4.8 Adverse Effects (Undesirable Effects)).

Immune reconstitution inflammatory syndrome.

In HIV infected patients with severe immune deficiency at the time of institution of CART, 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 weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders such as Graves' disease and autoimmune hepatitis 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). The pharmacokinetics of Intelence have not been studied in patients with severe hepatic impairment (Child-Pugh score C) (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Since the renal clearance of etravirine is negligible (< 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No special precautions or dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Experience in geriatric patients is limited. In the Phase III trials, 6 patients aged 65 years or older and 53 patients aged 56-64 years received Intelence. The type and incidence of adverse events in patients > 55 years of age were similar to the ones in younger patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of etravirine have not been established in children or adolescents. Etravirine studies are ongoing in HIV-1 infected children and adolescents (between the ages of 6 and 17 years, inclusive).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicinal products that affect etravirine exposure.

Etravirine is metabolised by cytochrome P450 (CYP) 3A4, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products that induce CYP3A4, CYP2C9 or CYP2C19 may increase the clearance of etravirine resulting in lowered plasma concentrations of etravirine. Co-administration of Intelence and medicinal products that inhibit CYP3A4, CYP2C9 or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine.

Medicinal products that are affected by the use of etravirine.

Etravirine is an inducer of CYP3A4. Co-administration of Intelence with medicinal products primarily metabolised by CYP3A4 may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects. Etravirine is an inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein but not a substrate. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19 or transported by P-glycoprotein may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or adverse events profile.
Drugs that are not recommended for co-administration with Intelence are included in Table 1. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Established and other potentially significant drug interactions with Intelence are included in Table 2. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of etravirine on fertility are available. Etravirine treatment of male and female rats at oral doses up to 500 mg/kg/day had no effect on fertility, at exposures approximately equivalent to those obtained in humans, based on AUC values.
(Category B1)
There are no adequate and well controlled studies with etravirine in pregnant women. Studies in animals have not shown evidence of developmental toxicity or an effect on reproductive function.
Developmental studies have been performed at oral doses of Intelence up to 1000 mg/kg/day in rats and up to 375 mg/kg/day in rabbits with no evidence of major embryofetal abnormality. Minor vertebral and rib anomalies were found in rat foetuses at 1000 mg/kg/day. The maternal plasma exposures (AUC values) at the no observed effect levels (NOELS) were approximately equivalent in both species to those obtained in humans at the recommended clinical dose.
In the rat pre- and postnatal development study, development and reproductive performance of offspring was not affected by maternal treatment with etravirine at oral doses up to 500 mg/kg/day. The maximum plasma exposures achieved in rats were approximately half those obtained in humans at the recommended clinical dose.
Intelence (200 mg b.i.d.), evaluated in combination with other antiretroviral agents in a study of 15 pregnant women during the second and third trimesters of pregnancy and postpartum, demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum, and less so for unbound etravirine exposure (see Section 5.2 Pharmacokinetic Properties).
Etravirine was detectable in maternal cord blood.
Given the increased etravirine exposure during pregnancy, caution should be applied for those pregnant patients that require concomitant medications or have comorbidities that may further increase etravirine exposure (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Intelence should be used during pregnancy only if the potential benefit justifies the potential risk.
 Etravirine is excreted in human milk. Because of both the potential for HIV transmission and the potential for adverse events in breast-feeding infants, mothers should be instructed not to breastfeed if they are receiving Intelence.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Intelence on the ability to drive or operate machines have been performed. There is no evidence that Intelence may alter the patient's ability to drive and operate machines, however, the adverse drug reaction profile of Intelence should be taken into account (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical trials.

The safety assessment is based on all data from 1203 patients in the Phase III placebo-controlled trials DUET-1 and DUET-2 in antiretroviral treatment-experienced HIV-1 infected adult patients, 599 of whom received Intelence (200 mg b.i.d.). In these pooled trials, the median exposure for patients in the Intelence arm and placebo arm was 52.3 and 51.0 weeks, respectively.
The most frequently reported adverse drug reactions (ADRs) (≥ 5%) that were at least grade 2 in severity were rash (10.0% in the Intelence arm and 3.5% in the placebo arm), diarrhoea (7.0% in the Intelence arm and 11.3%), hypertriglyceridaemia (6.3% in the Intelence arm and 4.3% in the placebo arm) and nausea (5.2% in the Intelence arm and 4.8% in the placebo arm) (see Table 3).
The majority of the ADRs reported during treatment with Intelence were grade 1 to 2 in severity. Grade 3 or 4 ADRs were reported in 22.2% and 17.2% of the Intelence and placebo treated patients, respectively. The most commonly reported grade 3 or 4 ADRs were hypertriglyceridaemia (4.2% in the Intelence arm and 2.3% in the placebo arm) and hypercholesterolaemia (2.2% in the Intelence arm and 2.3% in the placebo arm), renal failure (2.0% in the Intelence arm and 1.2% in the placebo arm) and anaemia (1.7% in the Intelence arm and 1.3% in the placebo arm). For treatment emergent clinical laboratory abnormalities (grade 3 or 4) reported in greater than or equal to 2% of Intelence treated patients (see Table 4: Treatment emergent laboratory abnormalities). All other grade 3 and/or 4 ADRs were reported in less than 1.5% of the Intelence treated patients. 5.2% of patients in the Intelence arm discontinued treatment due to ADRs compared to 2.6% of patients in the placebo arm. The most common ADRs leading to discontinuation was rash (2.2% in the Intelence arm versus 0% in the placebo arm).
Rash was most frequently mild to moderate, generally macular to maculopapular or erythematous, mostly occurred in the second week of therapy and was infrequent after week 4. Rash was mostly self-limiting and generally resolved within 1-2 weeks on continued therapy (see Section 4.4 Special Warnings and Precautions for Use). The incidence of rash was higher in women compared to men in the Intelence arm in the DUET trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men). In patients with a history of NNRTI related rash, there was no apparent increased risk for the development of Intelence related rash compared to patients without a history of NNRTI related rash.
ADRs of moderate intensity or greater (≥ grade 2) and reported in ≥ 1% of patients treated with Intelence are summarised in Table 3. The ADRs are listed by system organ class (SOC) and frequency. Laboratory abnormalities considered ADRs are included in Table 4 (see Treatment emergent grade 3 to 4 laboratory abnormalities reported in ≥ 2% of patients).
Treatment-emergent ADRs occurring in less than 1% of patients (n = 599) receiving Intelence and of at least moderate intensity (≥ Grade 2) are listed below by body system.

Body as a whole.

Sluggishness.

Cardiovascular system.

Angina pectoris, atrial fibrillation.

Digestive system.

Abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis.

Immune system.

Drug hypersensitivity, immune reconstitution syndrome.

Liver and biliary system.

Hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis.

Metabolic and nutritional.

Anorexia, dyslipidaemia.

Nervous system.

Paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor.

Respiratory system.

Exertional dyspnea, bronchospasm.

Skin and appendages.

Prurigo, hyperhidrosis, dry skin, swelling face.

Special senses.

Blurred vision, vertigo.

Urogenital system.

Gynecomastia.

Psychiatric.

Sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares.
Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic oedema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of patients. Stevens-Johnson syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare; < 0.01%) have been reported during clinical development with Intelence.

Laboratory abnormalities in treatment-experienced patients.

Treatment-emergent Grade 3 to Grade 4 laboratory abnormalities, considered ADRs, reported in ≥ 2% of adult patients treated with Intelence are presented in Table 4.

Lipodystrophy.

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see Section 4.4 Special Warnings and Precautions for Use).

Immune reconstitution inflammatory syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (immune reconstitution inflammatory syndrome). Autoimmune disorders such as Graves' disease and autoimmune hepatitis have also been reported in the context of Immune Reconstitution syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Additional information on special population.

Patients co-infected with hepatitis B and/or hepatitis C virus.

Among co-infected patients (n=139) in the pooled analysis for DUET-1 and DUET-2, grade 3 or 4 elevations in AST developed in 9.7% of the 72 patients in the Intelence arm and in 6.0% of the 67 patients in the placebo arm; and grade 3 or 4 elevations in ALT developed in 11.1% of patients in the Intelence arm and in 7.5% of patients in the placebo arm. Among co-infected patients, 1.4% of those treated with Intelence and 2.9% in the placebo arm discontinued because of liver or biliary system disorders. Standard clinical monitoring of patients with chronic hepatitis is considered adequate.

Postmarketing experiences.

The following events have been identified during the postmarketing use of Intelence. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders.

Fatal cases of toxic epidermal necrolysis have been reported. Severe hypersensitivity reactions including DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) have been reported and were characterized by rash, constitutional findings, and infrequently organ dysfunction, including hepatic failure (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis.

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

There is no specific antidote for overdose with Intelence. Human experience of overdose with Intelence is limited. Treatment of overdose with Intelence consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Emesis is not recommended due to the risks of aspiration. Administration of activated charcoal may be used to remove unabsorbed active substance when it is expected that there is drug still in the upper gastrointestinal tract; for most overdoses this is within 1 hour of ingestion. Charcoal aspiration can be fatal, so the risk versus benefit of using activated charcoal should be considered. Please refer to the current Therapeutic Guidelines. Since etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: J05AG04.

Mechanism of action.

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA dependent and DNA dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine can bind in at least two conformationally distinct modes. Within a given binding mode, torsional flexibility of etravirine permits access to numerous conformational variants, while the compact design of etravirine permits repositioning and reorientation (translation and rotation) within the pocket. Etravirine does not inhibit the human DNA polymerases α, β and γ in vitro.

Antiviral activity in vitro.

Etravirine exhibits activity against laboratory strains and clinical isolates of wild type HIV-1 in acutely infected T cell lines, human peripheral blood mononuclear cells and human monocytes/ macrophages with median EC50 values ranging from 0.9 to 5.5 nanoM (i.e. 0.4 to 2.4 nanogram/mL).
Etravirine demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (subtype A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from 0.7 to 21.7 nanoM. These EC50 values are well below the 50% cellular toxicity concentration range of 15 to > 100 microM.
The EC50 value of etravirine for HIV-1 increases by a median factor of 5.8 in the presence of human serum.
No antagonism is observed between etravirine and any of the studied antiretrovirals. Etravirine shows additive antiviral activity in combination with the protease inhibitors (PIs) amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, tipranavir and saquinavir; the nucleoside and nucleotide reverse transcriptase inhibitors (N(t)RTIs) zalcitabine, didanosine, stavudine, abacavir and tenofovir; the NNRTIs efavirenz, delavirdine and nevirapine; the fusion inhibitor enfuvirtide; the integrase strand transfer inhibitor raltegravir and the CCR5 antagonist maraviroc. Etravirine shows additive to synergistic antiviral activity in combination with the NRTIs emtricitabine, lamivudine and zidovudine.

Resistance in vitro.

Etravirine resistant strains were selected in cell culture from wild type HIV-1 of different origins and subtypes and from NNRTI resistant HIV-1. Reduced susceptibility to etravirine generally required multiple substitutions in the reverse transcriptase (RT), with the following observed most frequently: L100I, E138K, E138G, V179I, Y181C and M230I.
In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patients with virologic failure to the Intelence containing regimen were V179F, V179I, and Y181C, which usually emerged in a background of multiple other NNRTI resistance associated mutations (RAMs). In all the trials conducted with Intelence in HIV-1 infected patients, the following mutations emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y.

Cross resistance in vitro.

In a panel of HIV-1/HXB2 mutants with well defined single or multiple amino acid substitutions in the RT associated with NNRTI resistance, including the most commonly found K103N, 56/65 isolates with a single substitution, 18/40 with a double substitution and 6/21 with a triple substitution remained susceptible to etravirine (≤ 3-fold change in EC50). The single amino acid substitutions with highest resistance to etravirine were Y181I (13-fold change in EC50) and Y181V (17-fold change). Mutant strains with a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, M230L) had cross resistance between etravirine and efavirenz. Highest levels of resistance were observed with the combination of substitutions V179F + Y181C (187-fold change), V179F + Y181I (123-fold change) or V179F + Y181C + F227C (888-fold change).
The antiviral activity of etravirine in cell culture against 35 of 39 HIV-1 strains with multiple amino acid substitutions associated with resistance to N(t)RTIs and/or PIs was comparable to that observed against wild type HIV-1.
In a panel of 6171 clinical isolates resistant to at least one NNRTI, 37.3% were resistant to etravirine, and 78.8%, 87.4% and 95.3% were resistant to delavirdine, efavirenz and nevirapine, respectively (resistance defined as a fold change > the respective biological cut-off for the assay).
The treatment of patients with delavirdine, efavirenz or nevirapine following virologic failure of an etravirine containing regimen is not recommended.

Resistance in vivo.

In DUET-1 and DUET-2, the presence at baseline of 3 or more of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S (Intelence RAMs) was associated with a decreased virologic response to Intelence (see Table 5). These individual mutations occurred in the presence of other NNRTI RAMs. V179F was never present without Y181C.
K103N, which was the most prevalent NNRTI mutation in DUET-1 and DUET-2 at baseline, was not identified as a mutation associated with resistance to Intelence. The presence of this mutation did not affect the response in the Intelence arm.
Baseline etravirine phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline etravirine phenotype are shown in Table 6. These baseline phenotype groups are based on the select subject populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for Intelence. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment experienced patients.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.

Clinical trials.

The evidence of efficacy of Intelence is based on the analyses of 48 week data from 2 ongoing, randomised, double blinded, placebo controlled, Phase III trials DUET-1 (TMC125-C206) and DUET-2 (TMC125-C216). The primary objective of the trials was to show the superiority of TMC125 compared to placebo as part of an antiretroviral therapy (ART) containing TMC114/RTV and an investigator selected OBR, in the proportion of subjects with undetectable plasma viral load values (< 50 copies/mL) at Week 24.
The primary efficacy parameter of the DUET-1 and DUET-2 trials was the proportion of subjects with confirmed undetectable viral load (< 50 copies/mL) at week 24 according to the TLOVR (time to loss of virologic response) imputation algorithm.
These trials were identical in design, and similar efficacy for Intelence was seen in each trial. The results below are pooled data from the two trials.
Treatment experienced HIV-1 infected patients who had plasma HIV-1 RNA > 5,000 copies/mL and had 1 or more NNRTI resistance associated mutations at screening or from prior genotypic analysis (i.e. archived resistance) were enrolled. These patients also had 3 or more of the following primary PI mutations: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S or L90M at screening, and were on a stable antiretroviral regimen for at least 8 weeks. Randomisation was stratified by the intended use of enfuvirtide (ENF) in the background regimen (BR), previous use of darunavir/ ritonavir and screening viral load. This analysis included 612 patients in DUET-1 and 591 patients in DUET-2 who had completed 48 weeks of treatment or discontinued earlier.
At 48 weeks, the virologic response rate was evaluated in patients receiving Intelence (200 mg b.i.d.) in addition to a BR versus patients receiving placebo in addition to a BR. The BR consisted of darunavir/ ritonavir 600/100 mg b.i.d. and at least 2 other investigator selected antiretroviral drugs (N[t]RTIs with or without ENF). 45.6% of patients in the Intelence arm and 46.9% of patients in the placebo arm used ENF in the underlying antiretroviral therapy. 25.5% of patients in the Intelence arm used ENF for the first time (de novo), compared with 26.5% of patients in the placebo arm. 20.0% of patients in the Intelence arm re-used ENF, compared with 20.4% of patients in the placebo arm. Virologic response was defined as achieving a confirmed undetectable viral load (< 50 HIV-1 RNA copies/mL). In the pooled analysis for DUET-1 and DUET-2, demographics and baseline characteristics were balanced between the Intelence arm and the placebo arm. Table 7 describes the demographic and baseline disease characteristics of the patients in the Intelence arm and patients in the placebo arm.
Efficacy results at 48 weeks for patients in the Intelence arm and patients in the placebo arm for the total study population (pooled DUET-1 and DUET-2) are shown in Table 8.
The proportion of patients with confirmed viral load < 50 copies/mL at all time points up to Week 48, in the overall population according to the (Time to Loss of Virologic Response) TLOVR imputation algorithm, is presented in Figure 1.
In the total study population, through 48 weeks of treatment, the proportion of patients with < 400 HIV-1 RNA copies/mL in the arm receiving Intelence was 71.5% compared with 47.4% in the placebo arm. At Week 48, the mean decrease in plasma HIV-1 RNA from baseline at Week 48 were -2.25 log10 copies/mL in the arm receiving Intelence and -1.49 log10 copies/mL for the placebo arm. The change from baseline in log10 viral load at all time points is also presented graphically in Figure 2. Similar results were seen across the 2 DUET studies.
Intelence also showed an additional benefit over placebo in CD4+ cell count increase from baseline: 98.2 x 106 cells/L versus 72.9 x 106 cells/L, respectively. A graphical presentation of the mean change in CD4 cell count from baseline is provided in Figure 3.
As primary analysis method, the Cochran Mantel Haenszel test controlling for the stratification factors (use of ENF in the underlying ART, previous use of darunavir, and baseline plasma viral load) was applied to test the difference between the treatment groups at 24 weeks.
Because the effect of the Intelence treatment was expected to be different between subjects who were using ENF de novo in the optimised background regimen (OBR) and the subjects who were not using or re-using ENF, it was first tested whether there was a significant interaction effect between Intelence and ENF use.
Since there was a significant interaction effect between treatment and ENF, the primary analysis was done for 2 ENF strata (patients re-using or not using ENF versus patients using ENF de novo). The week 48 results from the pooled analysis of DUET-1 and DUET-2 demonstrated that the Intelence arm was superior to the placebo arm irrespective of whether ENF was used de novo or not. In the population of patients who either re-used or did not use ENF, the proportion of patients with < 50 HIV-1 RNA copies/mL in this subgroup was 57.0% in the Intelence arm and 33.0% in the placebo arm (a difference (95% CI) of 24.0% (17.6%; 30.3%)). In the group of patients that used ENF de novo, 71.2% of patients in the Intelence arm reached < 50 HIV-1 RNA copies/mL compared to 58.5% of patients in the placebo arm (a difference (95% CI) of 12.7% (2.3%; 23.2%)).
At week 48, 35 patients (5.8%) in the Intelence arm reached the endpoint of AIDS defining illness or death compared to 59 (9.8%) patients in the placebo arm.
In the population of patients who either re-used or did not use ENF, through 48 weeks of treatment, the proportion of patients with a decrease in HIV-1 RNA versus baseline of > 1.0 log10 in the arm receiving Intelence compared to placebo was 71.3% and 42.9%, respectively. In addition, the mean decrease in plasma HIV-1 RNA from baseline at Week 48 was -2.13 log10 copies/mL in the arm receiving Intelence and -1.23 log10 copies/mL for the placebo arm. Intelence also showed an additional benefit over placebo in CD4+ cell count increase from baseline: 85.7 x 106 cells/L versus 59.2 x 106 cells/L, respectively.
In the population of patients using ENF de novo, through 48 weeks of treatment, the proportion of patients with a decrease in HIV-1 RNA versus baseline of > 1.0 log10 in the arm receiving Intelence compared to placebo, was 83.0% and 74.8%, respectively. In addition, the mean decrease in plasma HIV-1 RNA from baseline at Week 48 was -2.60 log10 copies/mL in the arm receiving Intelence and -2.22 log10 copies/mL for the placebo arm. The CD4+ cell count increase from baseline was 134.5 x 106 cells/L in the Intelence arm versus 111.4 x 106 cells/L in the placebo arm.
The added benefit of etravirine when combined with a PI is not only observed with darunavir/ ritonavir, as this was also seen when it was combined with LPV/rtv in a randomised, controlled, partially blind, phase IIb trial, TMC125-C223. Patients included had documented genotypic evidence of resistance (either at screening or historically) to currently available NNRTIs, at least 3 primary PI mutations at screening and previous NRTI experience. Patients were randomised to the control arm (standard of care regimen consisting of at least 3 approved drugs (NRTIs and/or PIs and/or enfurvitide in any combination)), Intelence 400 mg b.i.d. or Intelence 800 mg b.i.d in a 1:2:2 ratio. The 800 mg dose used in this study is equivalent to the 200 mg dose used in the Phase III studies.
Results from this trial showed responses in the Intelence treatment group were statistically superior to the control group. This clinical evidence confirmed the in vitro virologic profile of the compound and demonstrated that Intelence is an active and potent treatment option for patients with NNRTI resistance.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult treatment experienced HIV-1 infected patients. Exposure to etravirine was slightly lower in HIV-1 infected patients than in healthy subjects. See Figure 4.

Absorption.

An intravenous formulation of etravirine is unavailable, thus, the absolute bioavailability of Intelence is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hours. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that are known to increase gastric pH.

Effect of food on absorption.

The exposure to etravirine is similar when taken following a standard normal caloric meal (561 kcal) or high fat high caloric meal (1160 kcal). When compared to administration following a standard normal caloric meal, exposures decreased when etravirine was taken before a standard normal caloric meal (17%), after a croissant (20%) or fasted (51%). Therefore, to achieve optimal exposure, Intelence should be taken following a meal (see Section 4.2 Dose and Method of Administration).

Distribution.

Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and α1-acid glycoprotein (94.5-97.7%) at physiological concentrations in vitro. The distribution of etravirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism.

In vitro experiments with human liver microsomes (HLMs) and E. coli systems expressing recombinant human CYP enzymes indicate that etravirine primarily undergoes oxidative metabolism by the hepatic cytochrome CYP450 (CYP3A) system and, to a lesser extent, by the CYP2C family followed by glucuronidation.

Excretion.

After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of 14C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hours.

Special populations.

Children and adolescents.

The pharmacokinetics of etravirine in paediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see Section 4.2 Dose and Method of Administration).

Elderly.

Population pharmacokinetic analysis in HIV infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18 to 77 years) evaluated (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Gender.

No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in the studies.

Race.

Population pharmacokinetic analysis of etravirine in HIV infected patients indicated that race had no apparent effect on the exposure to etravirine.

Renal impairment.

The pharmacokinetics of etravirine have not been studied in patients with renal insufficiency. Results from a mass balance study with radioactive 14C-etravirine showed that < 1.2% of the administered dose of etravirine is excreted in the urine. No unchanged drug was detected in urine so the impact of renal impairment on etravirine elimination is expected to be minimal. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh score A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh score B) hepatic impairment to 8 matched controls, the multiple dose pharmacokinetic disposition of etravirine was not altered in patients with mild to moderate hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Intelence has not been studied in patients with severe hepatic impairment (Child-Pugh score C) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatitis B and/or hepatitis C virus co-infection.

Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance for Intelence in HIV-1 infected patients with hepatitis B and/or C virus co-infection. Based upon the safety profile (see Section 4.8 Adverse Effects (Undesirable Effects)), no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Pregnancy and postpartum.

Study TMC114HIV3015 evaluated etravirine 200 mg twice daily in combination with other antiretroviral medicinal products in pregnant women during the second and third trimesters of pregnancy and postpartum.
Fifteen participants were enrolled, median (range) of maternal age was 26 (30-34) years, 11 were Black/African American, 2 were Hispanic and 2 were White. Median (range) BMI was 30.48 (23.4 to 47.5) kg/m2. All had Class A disease according to the CDC Classification System for HIV Infection 1993.
Lower apparent clearance (CL/F) was documented during the second and third trimesters of pregnancy compared to 6-12 weeks post-partum. Higher geometric mean values for total etravirine Cmax, AUC12h and Cmin were observed during pregnancy compared to postpartum (Table 9). The differences were less pronounced for unbound etravirine exposure.
Each participant served as her own control and for intra-individual comparisons, the total etravirine Cmin, Cmax and AUC12h values were 1.2, 1.4 and 1.4-fold higher, respectively, during the 2nd trimester of pregnancy compared to postpartum, and 1.1, 1.4 and 1.2-fold higher, respectively, during the 3rd trimester of pregnancy compared to postpartum.
The ratio of individual cord/ maternal intra-partum etravirine plasma concentrations ranged from 18.83% to 63.41%; with %CV of 35.5 (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Etravirine has tested negative in the in vitro Ames reverse mutation assay, in the in vitro chromosomal aberration assay in human lymphocytes, and in the in vitro clastogenicity genotoxicity assay mouse lymphoma assay, tested both in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice.

Carcinogenicity.

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 50, 200/100 and 400/200/100 mg/kg were administered to mice and doses of 70/50, 200/150/100 and 600/200/100 (males) and 70, 200/150 and 600/200/150 (females) mg/kg were administered to rats. Doses were reduced due to increased mortality. Etravirine was not carcinogenic in rats and in male mice. In female mice the incidence of hepatocellular adenomas and carcinomas was statistically significantly increased at all doses. Administration of etravirine did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular findings in female mice are considered to be of limited relevance to humans. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were between 0.8 and 0.9-fold (mice) and between 0.2 and 1.1-fold (rats), relative to those observed in humans at the recommended therapeutic dose (200 mg b.i.d.).

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, hypromellose, croscarmellose sodium, lactose monohydrate (100 mg tablets only).

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 30°C. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.

6.5 Nature and Contents of Container

Intelence 100 mg tablets are provided in high-density polyethylene (HDPE) plastic bottles containing 120 tablets and 3 desiccant pouches, fitted with a polypropylene (PP) child resistant closure*.
Intelence 200 mg tablets are provided in high-density polyethylene (HDPE) plastic bottles containing 60 tablets and 3 desiccant pouches, fitted with a polypropylene (PP) child resistant closure.
*Not currently marketed in Australia.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

269055-15-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes