Consumer medicine information

Stocrin

Efavirenz

BRAND INFORMATION

Brand name

Stocrin

Active ingredient

Efavirenz

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Stocrin.

SUMMARY CMI

STOCRIN®

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 using STOCRIN?

STOCRIN contains the active ingredient Efavirenz. STOCRIN is used to help treat HIV (Human Immunodeficiency Virus) infection. It is used in combination with other appropriate medicines used to treat the HIV virus.

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

2. What should I know before I use STOCRIN?

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

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

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

3. What if I am taking other medicines?

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

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

4. How do I use STOCRIN?

Your doctor will tell you how many tablets you need to take each day.

  • For adults and children weighing greater than or equal to 40 kg, the normal dose is 600 mg once a day. It is important that you are started and continue on this dose.
  • For children and teenagers 3 to 17 years old, the dose depends on body weight. Your child's doctor will decide the dose.

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

5. What should I know while using STOCRIN?

Things you should do
  • Report any changes in your condition to your doctor immediately to ensure any infections which occur due to your low immunity are treated promptly.
  • Continue to use safe sexual practices.
Things you should not do
  • Do not stop taking STOCRIN or change the dose without first checking with your doctor. Do not let yourself run out of medicine over weekends or on holidays.
Driving or using machines
  • Be careful driving or operating machinery until you know how STOCRIN affects you.
  • STOCRIN may cause dizziness, drowsiness or affect concentration in some people, especially during the first few days. Make sure you know how you react to STOCRIN before you drive a car or operate machinery.
Looking after your medicine

Keep your tablets in the original bottle, until it is time to take them
Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

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

6. Are there any side effects?

Like all medicines, STOCRIN can cause side effects, some may be serious, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of using STOCRIN.

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

STOCRIN®

Active ingredient: Efavirenz

Consumer Medicine Information (CMI)

This leaflet provides important information about using STOCRIN. 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 STOCRIN.

Where to find information in this leaflet:

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

1. Why am I using STOCRIN?

STOCRIN contains the active ingredient Efavirenz.

STOCRIN belongs to a group of medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It works by interrupting the formation of new HIV particles in already infected cells. When HIV is attacked by STOCRIN, the virus is not able to reproduce normally. This helps reduce the amount of virus in the blood. Although STOCRIN helps reduce the amount of virus in the blood and thus increases the CD4 count, it has not yet been shown to improve survival or slow the progression of the disease.

STOCRIN is used to help treat HIV (Human Immunodeficiency Virus) infection. It is used in combination with other appropriate medicines used to treat the HIV virus. Examples include protease inhibitors such as indinavir (Crixivan*) and nelfinavir (Viracept*). They also include nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT, Retrovir*) or lamivudine (3TC).

You may continue to develop infections or other illnesses associated with HIV disease while you are taking STOCRIN

2. What should I know before I use STOCRIN?

Warnings

Do not use STOCRIN if:

  • you have an allergy to STOCRIN or any of the ingredients listed at the end of this leaflet
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.
  • you are breast feeding or plan to breast feed.

If you are not sure whether you should start taking STOCRIN, talk to your doctor.

Check with your doctor if you:

  • you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes
  • you have or have had any medical conditions, especially the following:
    - liver disease, including hepatitis B or C
    - high cholesterol
    - mental illness
    - seizures or fits
  • you consume large amounts of alcohol or use recreational drugs
  • you are pregnant or intend to become pregnant
  • you are taking a medicine that contains efavirenz (e.g. ATRIPLA).
    STOCRIN should not be taken together with ATRIPLA or other medicines that contain efavirenz.
  • you have a higher risk of Torsade de Pointes.
    QTc Prolongation has been observed with the use of efavirenz. Your doctor may give you an alternative antiretroviral.

Pregnancy

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

If there is a need to take STOCRIN when you are pregnant, your doctor will discuss the possible risks and benefits to you and the unborn baby.

Women taking STOCRIN should avoid pregnancy during treatment and for 12 weeks after they've stopped taking treatment. Use barrier contraception even if you are using other methods (eg. oral contraceptive pill or other hormonal contraceptives).

If you become pregnant while taking STOCRIN or in the 12 weeks after you've stopped taking it, tell your doctor immediately.

Breastfeeding

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

It is possible that your baby can be infected with HIV through your breast milk.

Talk to your doctor about the best way to feed your baby.

Children

Do not give STOCRIN to children under 3 years of age or those who weigh less than 13 kg.

The safety and effectiveness of STOCRIN in these children have not been adequately established.

If you have not told your doctor about any of the above, tell them before you take any STOCRIN.

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?

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 should not be taken with STOCRIN as they may cause a life-threatening interaction. These include:

  • terfenadine and astemizole, antihistamines used for allergic conditions, including hayfever
  • cisapride, used to treat stomach reflux
  • triazolam (e.g.Halcion), used to treat anxiety, depression or for sleeplessness
  • midazolam (e.g. Hypnovel), used as a sedative before surgical procedures
  • some medicines used to treat migraine, including Cafergot*, Cafergot S*, Ergodryl*, Ergodryl Mono*, Dihydergot*, Migral*.
  • pimozide (not available in Australia)
  • bepridil (not available in Australia)
  • STOCRIN should not be taken together with ATRIPLA or other medicines that contain efavirenz.

In addition, STOCRIN should not be taken with St. John's wort (Hypericum perforatum), a herbal product sold as a dietary supplement, or products containing St. John's wort as it may decrease the effect of STOCRIN.

Do not take STOCRIN with elbasvir/grazoprevir as it may decrease the effect of elbasvir/grazoprevir.

STOCRIN should not be taken with voriconazole.

Some medicines and STOCRIN may interfere with each other. These include:

  • saquinavir (e.g.Invirase), amprenavir (e.g.Agenerase) and lopinavir/ritonavir (e.g.Kaletra) protease inhibitors used to treat HIV infection
  • telaprevir, simeprevir, boceprevir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir medicines used to treat hepatitis C
  • clarithromycin (e.g. Klacid), an antibiotic used to treat bacterial infections
  • rifampicin (e.g. Rifadin, Rimycin) and rifabutin (e.g. Mycobutin), antibiotics used to treat TB and infections caused by MAC
  • atovaquone/proguanil, (e.g. Malarone), or artemether/lumefantrine, medicines used to treat malaria
  • warfarin and acenocoumarol, medicines used to prevent blood clots
  • ethinyl oestradiol, used in some oral contraceptives
  • phenobarbitone, phenytoin and carbamazepine, medicines used to treat epilepsy and/or convulsions
  • methadone, a medicine used to treat opioid drug dependency
  • sertraline used to treat depression, obsessive compulsive disorder and panic disorder
  • bupropion, a medicine used to help you stop smoking
  • medicines affecting the immune system (e.g ciclosporin, tacrolimus or sirolimus). Your doctor might want to do some additional tests.
  • itraconazole
  • diltiazem or similar medicines (calcium channel blockers)
  • atorvastatin, pravastatin or simvastatin (lipid lowering medicines, also called statins)
  • medicines with known risk of Torsade de Pointes. QTc prolongation has been observed with the use of efavirenz. Your doctor may need to consider giving you different medicine.

These medicines may be affected by STOCRIN, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

STOCRIN is taken in combination with other medicines commonly used to help treat HIV-infection. These include the protease inhibitors such as indinavir (Crixivan*) and nelfinavir (Viracept*). They also include nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT, Retrovir*) or lamivudine (3TC). The optimal dose of indinavir, when given in combination with efavirenz, is not known.

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur when combination antiretroviral treatment is started. In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur.

Tell your doctor immediately if you notice any symptoms of infection or inflammation.

Make sure your doctor and pharmacist know about all of the medicines you are taking, as they have more information on medicines to be careful with or avoid while taking STOCRIN.

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

4. How do I use STOCRIN?

How much to take

Take STOCRIN only when prescribed by your doctor.

Your doctor will tell you how many tablets you need to take each day.

  • For adults and children weighing greater than or equal to 40 kg, the normal dose is 600 mg once a day. It is important that you are started and continue on this dose.
  • For children and teenagers 3 to 17 years old, the dose depends on body weight. Your child's doctor will decide the dose.

Carefully follow all directions given to you by your doctor.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle or box, ask your doctor or pharmacist for help.

How to take STOCRIN

Swallow STOCRIN with a glass of water.

Take STOCRIN on an empty stomach, preferably just before bedtime.

If you take STOCRIN with food, this can increase the risk of side effects.

When to take it

Take STOCRIN at about the same time each day.

Taking your tablets at the same time each day is important because keeping a constant level of STOCRIN in your body helps prevent resistance. Resistance means that the medicine may lose its effectiveness over time.

Your doctor may ask you to take STOCRIN at bedtime to avoid or reduce certain side effects, such as dizziness and sleepiness.

How long to take it

STOCRIN helps control your HIV infection but does not cure it. Therefore, STOCRIN must be taken every day. Continue taking STOCRIN for as long as your doctor prescribes.

Do not stop taking STOCRIN or change the dose without first checking with your doctor. Do not let yourself run out of medicine over weekends or on holidays.

If you have a break in therapy or reduce your dose temporarily, the virus may develop resistance and therefore STOCRIN may no longer be effective.

If, for any reason, your therapy with STOCRIN is interrupted or stopped, tell your doctor.

If you forget to use STOCRIN

If you miss a dose, take it as soon as you remember, and then go back to taking your tablet as you would normally. However, if it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

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

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you use too much STOCRIN

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

You should immediately:

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

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

5. What should I know while using STOCRIN?

Things you should do

  • Report any changes in your condition to your doctor immediately.
  • This is to make sure that any infections which occur due to your low immunity (called opportunistic infections) are treated promptly.
  • Continue to use safe sexual practices.
    STOCRIN has not been shown to decrease the chance of transmitting HIV to others through sexual contact or blood contamination.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking STOCRIN.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking STOCRIN.

Things you should not do

  • Do not stop taking STOCRIN or change the dose without first checking with your doctor. Do not let yourself run out of medicine over weekends or on holidays.

If you have a break in therapy or reduce your dose temporarily, the virus may develop resistance and therefore STOCRIN may no longer be effective.

If, for any reason, your therapy with STOCRIN is interrupted or stopped, tell your doctor.

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

Driving or using machines

Be careful driving or operating machinery until you know how STOCRIN affects you.

STOCRIN may cause dizziness, drowsiness or affect concentration in some people, especially during the first few days. Make sure you know how you react to STOCRIN before you drive a car or operate machinery. If you drink alcohol, dizziness or drowsiness may be worse.

Looking after your medicine

  • Keep your tablets in the original bottle, until it is time to take them.

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

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

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking STOCRIN, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

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?

STOCRIN helps most people with HIV infection, but it may have unwanted side effects. All medicines can have side effects.

Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Frequently it is difficult to tell whether side effects are the result of taking STOCRIN, effects of the HIV disease or side effects of other medicines you may be taking. For this reason, it is very important to inform your doctor of any change in your condition. Your doctor may want to change your dose or advise you to stop taking STOCRIN.

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

Common side effects in adults

Less serious side effectsWhat to do

Tell your doctor if you notice any of the following and they worry you:

  • skin rash or itchiness or increased sensitivity to sunlight
  • dizziness, tiredness, or sleepiness
  • nausea
  • stomach pain
  • headache
  • inability to concentrate
  • abnormal dreaming
  • difficulty sleeping
  • breast enlargement in men
  • increased fat appearing in areas such as the back of the neck, breasts, stomach and/or back
  • loss of body fat from areas such as face, arms and/or legs
  • changes in your co-ordination or ability to balance
  • flushing
  • tremors
  • ringing in the ears
Speak to your doctor if you have any of these common side effects and they worry you.

Some of these are the more common side effects of STOCRIN. They generally resolve after the first few weeks. Taking STOCRIN at night may help to reduce some of these side effects.

Some of these side effects may be worse if you:

  • drink alcohol
  • take medicines for certain mental illnesses, including depression, schizophrenia, psychoses, anxiety
  • take recreational drugs

Common side effects in children 3 to 16 years old

Less serious side effectsWhat to do

Tell your doctor if you notice any of the following and they worry you:

  • skin rash or itchiness or increased sensitivity to sunlight
  • dizziness
  • headache
  • fever
  • nausea or vomiting
  • stomach pain, diarrhoea
  • cough
  • aches or pains
  • increased fat appearing in areas such as the back of the neck, breasts, stomach and/or back
  • loss of body fat from areas such as face, arms and/or legs
Speak to your doctor if you have any of these common side effects and they worry you.

These are the more common side effects of STOCRIN in children.

Serious side effects in adults and children

Serious side effectsWhat to do

Tell your doctor immediately if you notice any of the following:

  • severe dizziness, spinning sensation
  • tingling or numbness of the hands or feet
  • blurred vision
  • mental changes, including seeing, feeling or hearing things that are not there (also called hallucinations)
  • mood changes, including depression, suicidal thoughts or actually committing suicide, angry behaviour, strange thoughts, anxiousness, and catatonia (condition in which the patient is rendered motionless and speechless for a period). People who have or have had mental illnesses appear to be at greater risk of these effects.
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.

Some nervous system symptoms (e.g., confusion, slow thoughts and physical movement, and delusions [false beliefs] or hallucinations [seeing or hearing things that others do not see or hear]) may occur months to years after beginning STOCRIN therapy.

Because some of these may be serious side effects, you may need urgent medical attention.

Other Serious Side effects

Other serious side effectsWhat to do
  • any severe skin reaction
  • pinkish, itchy swellings on the skin, also called hives or nettlerash
  • fainting
  • fast or irregular heart beat
  • wheeziness due to tightness in the chest
  • convulsions or fits
  • liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and/or dark coloured urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What STOCRIN contains

Active ingredient
(main ingredient)		efavirenz
Other ingredients
(inactive ingredients)		lactose monohydrate
magnesium stearate
croscarmellose sodium
cellulose-microcrystalline
sodium lauryl sulfate
hyprolose
hypromellose
titanium dioxide
macrogol 400
iron oxide yellow CI 77492(50 mg, 200 mg and 600 mg tablets only)
carnauba wax

STOCRIN does not contain gluten, sucrose, tartrazine or any other azo dyes.

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

What STOCRIN looks like

STOCRIN is available in three strengths of tablets:

50 mg tablet - yellow round tablet with "113" on one side & plain on the other (AUST R 125198*)

200 mg tablet - yellow round tablet with "223" on one side & plain on the other (AUST 125199)

300mg tablet - white capsule-shaped tablet with “224” in purple on both sides (AUST R 82787* & AUST R 82786*)

600 mg - yellow capsule-shaped tablet with "225" debossed on one side & plain on the other (AUST R 82789)

*These pack sizes not currently available in Australia

Who distributes STOCRIN

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road,
Macquarie Park, NSW 2113, Australia

This leaflet was prepared on 27 January 2023.

CCPPI-MK0831-MF-062022

RCN: 000024479-AU

Copyright © 2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Stocrin

Active ingredient

Efavirenz

Schedule

S4

 

1 Name of Medicine

Efavirenz.

2 Qualitative and Quantitative Composition

Efavirenz is a white to slightly pink crystalline powder.
Stocrin is available as tablets for oral administration. Each Stocrin tablet contains 50, 200, 300 or 600 mg of efavirenz.

List of excipients with known effect.

Contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Stocrin 50 mg tablets are yellow, round shaped tablets with "113" on one side and plain on the other.
Stocrin 200 mg tablets are yellow, round shaped tablets with "223" on one side and plain on the other.
Stocrin 300 mg tablets are white, capsular film-coated tablets with "224" in purple ink on both sides.
Stocrin 600 mg tablets are yellow, capsular film-coated tablets with "225" in purple ink on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Stocrin is indicated for use in combination with other antiviral agents for the treatment of HIV-1 infection in adults and children (see Section 5.1 Pharmacodynamic Properties, Use in children).

4.2 Dose and Method of Administration

Stocrin should be taken in the fasted state, preferably at bedtime. Food increases the bioavailability of Stocrin and this may be associated with a higher frequency of side effects.
In order to improve the tolerability of nervous system side effects, bedtime dosing is recommended during the first two to four weeks of therapy and in patients who continue to experience these symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).

Concomitant antiretroviral therapy.

Stocrin must be given in combination with other antiretroviral medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Adults.

The recommended dosage of Stocrin in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs) is 600 mg orally, once daily.

Adolescents and children (17 years and under).

The recommended dose of Stocrin in combination with a protease inhibitor and/or NRTIs for patients 17 years of age and under is described in Table 1. Stocrin tablets should only be administered to children who are able to reliably swallow tablets. Stocrin tablets have not been adequately studied in children under the age of 3 years or children weighing less than 13 kg (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

4.3 Contraindications

Stocrin is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Stocrin is contraindicated with elbasvir/grazoprevir due to the expected significant decreases in elbasvir and grazoprevir plasma concentrations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This effect is due to an induction of CYP3A4 by efavirenz and is expected to result in the loss of virologic response of elbasvir/grazoprevir.
Stocrin should not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot derivatives because competition for CYP3A4 by efavirenz could result in reduction of metabolism of these drugs and create the potential for serious and/or life threatening adverse events (e.g. cardiac arrhythmias, prolonged sedation or respiratory depression).
Coadministration of Stocrin with voriconazole is contraindicated. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

St. John's wort (Hypericum perforatum).

Patients on efavirenz should not concomitantly use products containing St. John's wort (Hypericum perforatum) since it may be expected to result in reduced plasma concentrations of efavirenz. This effect is due to an induction of CYP3A4 and may result in loss of therapeutic effect and development of resistance.

4.4 Special Warnings and Precautions for Use

Stocrin must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when Stocrin is administered as monotherapy.
When prescribing drugs concomitantly with Stocrin, physicians should refer to the corresponding manufacturer's product information.
If any antiretroviral medication in a combination regimen is interrupted because of suspected intolerance, serious consideration should be given to simultaneous discontinuation of all antiretroviral medications. The antiretroviral medications should be restarted at the same time upon resolution of the intolerance symptoms. Intermittent monotherapy and sequential reintroduction of antiretroviral agents is not advisable because of the increased potential for selection of drug resistant mutant virus.
Coadministration of Stocrin with combination products that contain efavirenz (e.g. Atripla) is not recommended, unless needed for dose adjustment (e.g. with rifampin).
Malformations have been observed in foetuses from efavirenz treated animals. There are no adequate and well controlled studies of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, more than 700 pregnancies with first trimester exposure to Stocrin as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. Retrospectively in this registry, isolated cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established (see Section 4.6 Fertility, Pregnancy and Lactation). Therefore, pregnancy should be avoided in women receiving Stocrin. Barrier contraception should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

QTc prolongation.

QTc prolongation has been observed with the use of efavirenz (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Consider alternatives to Stocrin when coadministered with a drug with a known risk of torsade de pointes or when administered to patients at higher risk of torsade de pointes.

Psychiatric/ nervous system symptoms.

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences. There have been reports (approximately 1-2 per thousand Stocrin treated patients) of delusions and inappropriate behaviour, predominantly in patients with a history of mental illness or substance abuse. Severe acute depression (including suicidal ideation/ attempts) has also been infrequently reported in both Stocrin treated and control treated patients. There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behaviour, and catatonia although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients who experience these symptoms should contact their doctor immediately because discontinuation of Stocrin may be required.
Fifty-two percent of patients receiving Stocrin reported central nervous system and psychiatric symptoms. These symptoms included, but were not limited to, dizziness, impaired concentration, somnolence, abnormal dreams and insomnia. In controlled trials, these symptoms were severe in 2.9% of patients receiving Stocrin 600 mg QD and in 1.3% of patients receiving control regimens. In clinical trials, 2.7% of Stocrin treated patients discontinued therapy because of nervous system symptoms. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks. Patients should be informed that these symptoms are likely to improve with continued therapy. Dosing at bedtime improves the tolerability of these symptoms and is recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).
Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms, which are associated with increased efavirenz levels despite standard dosing of Stocrin. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to efavirenz use, and whether discontinuation of Stocrin is warranted.
Patients receiving Stocrin should be alerted to the potential for additive central nervous system effects when Stocrin is used concomitantly with alcohol or psychoactive drugs.
Patients should be informed that Stocrin may cause dizziness, impaired concentration and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Skin rash.

Mild to moderate rash has been reported in clinical trials with Stocrin and usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with Stocrin. The incidence of erythema multiforme or Stevens-Johnson syndrome was 0.14%. Stocrin should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Efavirenz is not recommended for patients who have had a life threatening cutaneous reaction (e.g. Stevens-Johnson syndrome). If therapy with Stocrin is discontinued, consideration should also be given to interrupting therapy with other antiretroviral agents to avoid development of drug resistant virus (see Section 4.8 Adverse Effects (Undesirable Effects)).
Rash was reported in 59 of 182 paediatric patients (32%) treated with Stocrin in three clinical trials for a median of 123 weeks. Rash was severe in 6 patients. The median time to onset of rash in paediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines prior to initiating therapy with Stocrin in children may be considered.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including Stocrin. During the initial phase of treatment, a patient whose immune system responds to CART may mount an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.

Special populations.

Efavirenz is not recommended for patients with moderate or severe hepatic impairment because of insufficient data to determine whether dose adjustment is necessary. Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering Stocrin to patients with hepatic impairment. Patients with mild liver disease may be treated with their normally recommended dose of Stocrin. Patients should be monitored carefully for adverse events. Laboratory tests should be performed to evaluate their liver disease at periodic intervals.
In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity.
Patients with underlying liver disease including chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population.
Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.
Stocrin tablets have not been adequately evaluated in children below 3 years of age or who weigh less than 13 kg. Evidence exists indicating that efavirenz may have altered pharmacokinetics in very young children. For this reason, efavirenz tablets should not be given to children less than 3 years of age (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Convulsions have been observed rarely in adult and paediatric patients receiving efavirenz, including in the presence of known medical history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolised by the liver, such as carbamazepine, phenytoin and phenobarbitone, may require periodic monitoring of plasma levels. Caution must be taken in any patient with a history of seizures.

Voriconazole.

Stocrin must not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Liver enzymes.

In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity monitoring of liver enzymes is recommended. In patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Stocrin needs to be weighed against the unknown risks of significant liver toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cholesterol.

Monitoring of cholesterol should be considered in patients treated with Stocrin (see Section 4.8 Adverse Effects (Undesirable Effects)).

Lipodystrophy and metabolic abnormalities.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsovisceral fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hypergylcaemia and hyperlactataemia. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Information for patients.

Patients should be informed that Stocrin is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that Stocrin therapy can reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
Patients should be informed that Stocrin may cause late-onset neurotoxicity (months to years after beginning efavirenz therapy), which includes ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium).
Patients should be advised to take Stocrin every day as prescribed. Stocrin must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician.
If therapy with Stocrin is interrupted for any reason, serious consideration should be given to stopping other antiretroviral agents. Likewise, if any concomitant antiviral therapy is stopped temporarily, therapy with Stocrin should also be stopped. All antiretroviral agents should be restarted at the same time.
Malformations have been observed in foetuses from efavirenz treated monkeys that received doses which resulted in plasma drug concentrations similar to those in humans given 600 mg/day (see Section 4.6 Fertility, Pregnancy and Lactation); therefore, pregnancy should be avoided in women receiving Stocrin. Barrier contraception should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives).
Stocrin may interact with some drugs, therefore patients should be advised to report to their doctor the use of any prescription or nonprescription medication, or herbal products, particularly St. John's wort.

Paediatric use.

Efavirenz has not been studied in paediatric patients below 3 months of age or who weigh less than 3.5 kg (see Section 5.1 Pharmacodynamic Properties).
The safety, pharmacokinetic profile, and virologic and immunologic responses of Stocrin (efavirenz) were evaluated in antiretroviral naive and -experienced HIV-1 infected paediatric patients 3 months to 21 years of age in three open label clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties). The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of grade 3 or 4 rash, in paediatric patients compared to adults (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

Insufficient numbers of elderly patients have been evaluated in clinical studies to determine whether they respond differently than younger patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with Stocrin. In vitro studies have demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolised by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.
Although potential interactions with terfenadine, astemizole, cisapride, midazolam, triazolam or ergot derivatives have not been studied, Stocrin should not be administered concurrently with these drugs because competition for CYP3A4 by efavirenz could result in reduction of their metabolism and create the potential for serious and/or life threatening adverse events (see Section 4.3 Contraindications). (See Table 2.)
Drugs which induce CYP3A4 activity (e.g. phenobarbitone, rifampicin, phenytoin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

QT prolonging drugs.

There is limited information available on the potential for a pharmacodynamic interaction between Stocrin and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz (see Section 5.1 Pharmacodynamic Properties). Consider alternatives to Stocrin when co-administered with a drug with a known risk of torsade de pointes.

Concomitant antiretroviral agents.

Amprenavir.

The AUC, Cmax and Cmin of amprenavir (1200 mg every 12 hours) were decreased when given with Stocrin (600 mg once daily) in HIV infected subjects. While the clinical significance of decreased amprenavir concentrations has not been established, the possibility of this interaction should be taken into consideration before choosing a regimen containing both Stocrin and amprenavir.

Fosamprenavir calcium.

For guidance on coadministration with fosamprenavir and ritonavir, the prescribing information for fosamprenavir calcium should be consulted.

Atazanavir.

Coadministration of Stocrin 600 mg with atazanavir resulted in substantial decreases in atazanavir exposure, necessitating dosage adjustment of atazanavir in combination with ritonavir.

Nelfinavir.

The AUC and Cmax of nelfinavir (750 mg every 8 hours) are increased by 20% and 21%, respectively, when given with Stocrin in uninfected volunteers. The combination was generally well tolerated and no dose adjustment is necessary when nelfinavir is administered in combination with Stocrin.

Indinavir.

When indinavir (800 mg every 8 hours) was given with Stocrin, the indinavir AUC and Cmax were decreased by approximately 31% and 16%, respectively, as a result of enzyme induction. The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg does not compensate for the increased indinavir metabolism due to efavirenz. No adjustment of the dose of Stocrin is necessary when given with indinavir.

Maraviroc.

Refer to the prescribing information for maraviroc for guidance on coadministration with Stocrin.

Raltegravir.

The AUC, Cmax, and Cmin of raltegravir (400 mg single dose) were decreased by 36%, 36%, and 21%, respectively, when given with efavirenz (600 mg once daily) compared to raltegravir alone. The mechanism of the interaction is induction of the UGT1A1 enzyme by efavirenz. No dose adjustment is necessary for raltegravir.

Ritonavir.

When Stocrin 600 mg (given once daily at bedtime) and ritonavir 500 mg (given every 12 hours) was studied in uninfected volunteers, the combination was not well tolerated and was associated with a higher frequency of adverse clinical experiences (e.g. dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Stocrin is used in combination with ritonavir.

Saquinavir.

When saquinavir soft gelatin capsules (1200 mg every 8 hours) was given with Stocrin to uninfected volunteers, saquinavir AUC and Cmax were decreased by 62% and 45-50%, respectively. Use of Stocrin in combination with saquinavir as the sole protease inhibitor is not recommended.

Saquinavir/ ritonavir.

No data are available on the potential interactions of Stocrin with the combination of saquinavir and ritonavir.

Lopinavir/ ritonavir.

When used in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in multiple protease inhibitor experienced subjects, increasing the dose of lopinavir/ ritonavir 33.3% from 400/100 mg (3 soft capsules) BID to 533/133 mg (4 soft capsules) BID yielded similar lopinavir plasma concentrations as compared to historical data of lopinavir/ ritonavir 400/100 mg BID.
For patients with extensive protease inhibitor experience, or phenotypic or genotypic evidence of significant loss of sensitivity toward lopinavir, dosage increase to 533/133 mg BID should be considered when coadministered with efavirenz.

Nucleoside analogue reverse transcriptase inhibitors.

Studies of the interaction between efavirenz and the combination of zidovudine and lamivudine were performed in HIV infected patients. No clinically significant pharmacokinetic interactions were observed. Specific drug interaction studies have not been performed with Stocrin and other NRTIs. Clinically significant interactions would not be expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

Non-nucleoside reverse transcriptase inhibitors.

No studies have been performed with Stocrin in combination with other NNRTIs.

HCV antivirals.

Boceprevir.

When efavirenz (600 mg once daily) was given with boceprevir (800 mg three times daily) the plasma trough concentration of boceprevir was decreased. The clinical outcome of this observed reduction has not been directly assessed.

Telaprevir.

Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. When telaprevir 1125 mg every 8 hours was administered with efavirenz 600 mg once daily, the AUC, Cmax, and Cmin of telaprevir were decreased by 18%, 14%, and 25% relative to telaprevir 750 mg every 8 hours administered alone and the AUC, Cmax, and Cmin of efavirenz were decreased by 18%, 24%, and 10%. Refer to the prescribing information for telaprevir for guidance on coadministration with Stocrin.

Simeprevir.

Concomitant administration of simeprevir with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz which may result in loss of therapeutic effect of simeprevir. Coadministration of simeprevir with Stocrin is not recommended. Refer to the product information for simeprevir for more information.

Elbasvir/grazoprevir.

Coadministration of Stocrin with elbasvir/grazoprevir reduces AUC and Cmax of elbasvir by 54% and 45%, respectively and AUC and Cmax of grazoprevir by 83% and 87%, respectively compared to elbasvir/grazoprevir alone. Concomitant administration of Stocrin with elbasvir/grazoprevir is contraindicated (see Section 4.3 Contraindications) because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A4 induction. Refer to the prescribing information for elbasvir/grazoprevir for more information.

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir.

Coadministration of efavirenz with a HCV treatment regimen containing velpatasvir has been shown to decrease velpatasvir exposure. Concomitant administration of sofosbuvir/velpatasvir with Stocrin decreased velpatasvir AUC, Cmax, and Cmin by 53%, 47%, and 57%, respectively, compared with sofosbuvir/velpatasvir alone. Coadministration of Stocrin with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended. Refer to the prescribing information for sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir for more information.

Antimicrobial agents.

Rifamycins.

Rifampicin reduced efavirenz AUC by 26% and Cmax by 20% in 12 uninfected volunteers. The dose of Stocrin should be increased to 800 mg/day when taken with rifampicin. No dose adjustment of rifampicin is recommended when given with Stocrin. In uninfected volunteers, the Cmax and AUC of rifabutin were decreased and rifabutin clearance was increased when rifabutin was given with Stocrin. The possibility of this interaction should be taken into consideration before choosing a regimen containing both Stocrin and rifabutin.
Coadministration of Stocrin with combination products that contain efavirenz (e.g. Atripla) is not recommended, unless needed for dose adjustment (e.g. with rifampicin).
Macrolide antibiotics.

Azithromycin.

Coadministration of single doses of azithromycin and multiple doses of Stocrin in uninfected volunteers did not result in any clinically significant pharmacokinetic interaction. No dosage adjustment is necessary when azithromycin is given in combination with Stocrin.

Clarithromycin.

Coadministration of 400 mg of Stocrin once daily with clarithromycin given as 500 mg every 12 hours for seven days resulted in a significant effect of efavirenz on the pharmacokinetics of clarithromycin. The AUC and Cmax of clarithromycin decreased 39% and 26%, respectively, while the AUC and Cmax of the clarithromycin hydroxymetabolite were increased 34% and 49%, respectively, when used in combination with Stocrin. The clinical significance of these changes in clarithromycin plasma levels is not known. In uninfected volunteers, 46% developed rash while receiving Stocrin and clarithromycin. No dose adjustment of Stocrin is recommended when given with clarithromycin. Alternatives to clarithromycin should be considered.
Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Stocrin.
Antifungal agents. No clinically significant pharmacokinetic interactions were seen when fluconazole and Stocrin were coadministered to uninfected volunteers. No dosage adjustment is necessary when the two drugs are used in combination. The potential for drug interactions with Stocrin and other imidazole antifungals, such as ketoconazole, has not been studied.

Voriconazole.

Stocrin should not be administered concurrently with voriconazole because Stocrin significantly decreases voriconazole plasma concentrations. The steady-state AUC and Cmax of voriconazole decreased by 77% and 61%, respectively, while the steady state AUC and Cmax of Stocrin increased by 44% and 38%, respectively. Coadministration of Stocrin and voriconazole is contraindicated.

Itraconazole.

Coadministration of efavirenz (600 mg orally once daily) with itraconazole (200 mg orally every 12 hours) in uninfected volunteers decreased the steady-state AUC, Cmax and Cmin of itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

Posaconazole.

Concomitant use of posaconazole and Stocrin should be avoided unless the benefit to the patient outweighs the risk.
Antimalarial agents. Concomitant administration of atovaquone/ proguanil with efavirenz should be avoided whenever possible.

Artemether/ lumefantrine.

Coadministration of efavirenz (600 mg once daily) with artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) resulted in a decrease in exposures (AUC) to artemether, dihydroartemisinin (active metabolite of artemether), and lumefantrine by approximately 51%, 46%, and 21%, respectively. Exposure to efavirenz was not significantly affected. Since decreased concentrations of artemether, dihydroartemisinin, or lumefantrine may result in a decrease of antimalarial efficacy, caution is recommended when Stocrin and artemether/ lumefantrine tablets are coadministered.

Lipid lowering agents.

Coadministration of efavirenz with the HMG-CoA reductase inhibitors atorvastatin, pravastatin, or simvastatin has been shown to reduce the plasma concentration of the statin in uninfected volunteers. Cholesterol levels should be periodically monitored. Dosage adjustments of statins may be required.

Other drug interactions.

Antacids/ famotidine. Neither aluminium/ magnesium hydroxide antacids nor famotidine altered the absorption of efavirenz in uninfected volunteers. These data suggest that alteration of gastric pH by other drugs would not be expected to affect efavirenz absorption.
Hormonal contraceptives.

Oral.

When an oral contraceptive (ethinyl estradiol 0.035 mg/norgestimate 0.25 mg once daily) and efavirenz (600 mg once daily) were coadministered for 14 days, efavirenz had no effect on ethinyl estradiol concentrations but plasma concentrations of norelgestromin and levonorgestrel, active metabolites of norgestimate, were markedly decreased in the presence of efavirenz (64%, 46%, and 82% decrease in norelgestromin AUC, Cmax and Cmin, respectively, and 83%, 80%, and 86% decrease in levonorgestrel AUC, Cmax, and Cmin, respectively). The clinical significance of these effects is not known. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.

Injection.

Limited information exists regarding efavirenz and injectable hormonal contraception. In a 3 month drug interaction study of depo-medroxyprogesterone acetate (DMPA) and efavirenz, plasma progesterone levels for all subjects remained below 5 nanogram/mL, consistent with suppression of ovulation.

Implant.

Decreased exposure of etonogestrel may be expected due to CYP3A4 induction by efavirenz, and there have been occasional postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Barrier contraception should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives).
Immunosuppressants. When an immunosuppressant metabolized by CYP3A4 (e.g. ciclosporin, tacrolimus, or sirolimus) is administered with efavirenz, decreased exposure of the immunosuppressant may be expected due to CYP3A4 induction. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Anticonvulsants.

Carbamazepine.

Coadministration of efavirenz (600 mg orally once daily) with carbamazepine (400 mg once daily) in uninfected volunteers resulted in a two way interaction. The steady-state AUC, Cmax and Cmin of carbamazepine decreased by 27%, 20% and 35%, respectively, while the steady-state AUC, Cmax and Cmin of efavirenz decreased by 36%, 21%, and 47%, respectively. The steady-state AUC, Cmax and Cmin of the active carbamazepine epoxide metabolite remained unchanged. Carbamazepine plasma levels should be monitored periodically. There are no data with coadministration of higher doses of either medicinal product; therefore, no dose recommendation can be made, and alternative anticonvulsant treatment should be considered.

Other anticonvulsants.

No data are available on the potential interactions of efavirenz with phenytoin, phenobarbital, or other anticonvulsants that are substrates of CYP450 isozymes. When efavirenz is administered concomitantly with these agents, there is a potential for reduction or increase in the plasma concentrations of each agent; therefore, periodic monitoring of plasma levels should be conducted. Specific interaction studies have not been performed with efavirenz and vigabatrin or gabapentin.
Methadone. Coadministration of efavirenz with methadone has resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Antidepressants. The Cmax, C24 and AUC of sertraline were decreased when given with Stocrin. The possibility of this interaction should be taken into consideration before choosing a regimen containing both Stocrin and sertraline. Sertraline dose increases should be guided by clinical response.
Bupropion. Increases in bupropion dose may be necessary when taken in combination with efavirenz and should be guided by clinical response, but should not exceed the maximum recommended dose. No adjustment of efavirenz is required.
Calcium channel blockers. Coadministration of efavirenz (600 mg orally once daily) with diltiazem (240 mg orally once daily) in uninfected volunteers decreases the steady-state AUC, Cmax and Cmin of diltiazem. Diltiazem dose adjustments should be guided by clinical response (refer to the Product Information for diltiazem).
Although the pharmacokinetic parameters of efavirenz were slightly increased (11%-16%), these changes are not considered clinically significant and, thus, no dosage adjustment is necessary for efavirenz when administered with diltiazem.
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of the CYP3A4 enzyme (e.g. verapamil, felodipine, nifedipine, nicardipine). When efavirenz is administered concomitantly with one of these agents, there is a potential for reduction in the plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the corresponding Product Information documents for the calcium channel blocker).
Cannabinoid test interaction. Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV infected volunteers who received Stocrin. Confirmation of positive screening tests for cannabinoids by a more specific method such as gas chromatography/ mass spectrometry is recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm or offspring of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were below those achieved in humans given therapeutic doses of efavirenz.
(Category D)
Malformations have been observed in 3 of 20 foetuses/ infants from efavirenz treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20-150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz. Anencephaly and unilateral anophthalmia were observed in one foetus, microphthalmia was observed in another foetus, and cleft palate was observed in a third foetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces foetal blood concentrations similar to maternal blood concentrations. Because teratogenic effects have been seen in primates at efavirenz exposures similar to those seen in the clinic at the recommended dose, pregnancy should be avoided in women receiving efavirenz. Barrier contraception should always be used in combination with other methods of contraception (e.g. oral or other hormonal contraceptives).
Efavirenz has been shown to cross the placenta in rats and rabbits and produces foetal blood concentrations of efavirenz similar to maternal concentrations. An increase in foetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg QD of efavirenz. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to, and AUC values approximately half of, those achieved in humans given 600 mg QD of efavirenz.
Pregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (for example oral or other hormonal contraceptives). Use of adequate contraceptive measures for 12 weeks after discontinuation of Stocrin is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz. Efavirenz should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus and there are no other appropriate treatment options. If a woman takes efavirenz during the first trimester of pregnancy or becomes pregnant while taking efavirenz, she should be informed of the potential harm to the foetus.
There are no adequate and well controlled studies in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, more than 700 pregnancies with first trimester exposure to Stocrin as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. In this registry, 4 retrospective reports (i.e. after the results of the pregnancy were known) of findings consistent with neural tube defects, including 3 cases of meningomyelocele have been reported. All 4 mothers were exposed to efavirenz containing regimens in the first trimester. Although a causal relationship of these events to the use of Stocrin has not been established, similar defects have been observed in preclinical studies of efavirenz.
 Efavirenz is secreted into the milk of lactating rats, and efavirenz also has been shown to pass into human breast milk. The use of Stocrin in lactating mothers is not recommended. Mothers should be instructed not to breastfeed if they are receiving Stocrin. It is recommended that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects on Ability to Drive and Use Machines

Patients should be informed that Stocrin may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial information.

Efavirenz was generally well tolerated in clinical trials. Efavirenz has been studied in over 9000 patients. In a subset of 1008 patients who received 600 mg efavirenz daily in combination with protease inhibitors and/or NRTIs in controlled clinical studies, the most frequently reported treatment related undesirable effects of at least moderate severity reported in at least 5% of patients were rash (11.6%), dizziness (8.5%), nausea (8.0%), headache (5.7%) and fatigue (5.5%). Nausea was reported with a higher frequency in the control groups. The most notable undesirable effects associated with efavirenz are rash, nervous system symptoms and psychiatric symptoms (see Section 4.4 Special Warnings and Precautions for Use).
Other, less frequent, clinically significant treatment related undesirable effects reported in all clinical trials include: allergic reaction, abnormal coordination, ataxia, confusion, stupor, vertigo, vomiting, diarrhoea, hepatitis, impaired concentration, insomnia, anxiety, abnormal dreams, somnolence, depression, abnormal thinking, agitation, amnesia, delirium, emotional lability, euphoria, hallucination, psychosis, and catatonia.
A few cases of pancreatitis have been described although a causal relationship with efavirenz has not been established.
The type and frequency of undesirable effects in children was generally similar to that of adult patients with the exception that rash was reported more frequently in children and was more often of higher grade than in adults.

Skin rash.

In clinical trials, 26% of patients treated with 600 mg Stocrin experienced new onset skin rash compared with 17% of patients treated in control groups. Skin rash was considered treatment related in 18% of patients treated with Stocrin. Grade 3 rash associated with blistering, moist desquamation, or ulceration occurred in less than 1% of patients treated with Stocrin. The incidence of grade 4 rash (erythema multiforme or Stevens-Johnson syndrome) was 0.14%. The discontinuation rate for rash in clinical trials was 1.7% (7/413).
Rash was reported in 59 of 182 paediatric patients (32%) treated with Stocrin in three clinical trials for a median of 123 weeks. Two (1.1%) paediatric patients experienced grade 3 rash (confluent rash with fever, generalised rash), and four (2.2%) paediatric patients had grade 4 rash (all erythema multiforme). Five paediatric patients (2.7%) discontinued from the study because of rash. The median time to onset of rash in paediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines prior to initiating therapy with Stocrin in children may be considered.
Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first two weeks of initiating therapy with Stocrin. In most patients, rash resolves with continuing therapy with Stocrin within one month. Stocrin can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Stocrin is restarted (see Section 4.4 Special Warnings and Precautions for Use).
Experience with Stocrin in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with Stocrin. Nine of these patients developed mild to moderate rash while receiving therapy with Stocrin, and two of these patients discontinued because of rash.
Skin rash was more prevalent in children receiving Stocrin than in adults.

Psychiatric symptoms.

Serious psychiatric adverse experiences have been reported in some patients treated with efavirenz. The following serious psychiatric events were reported in patients in controlled trials using regimens containing efavirenz (n = 1008) and control regimens (n = 635): severe depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), non-fatal suicide attempts (0.4%, 0%), aggressive behaviour (0.4%, 0.3%), paranoid reactions (0.4%, 0.3%) and manic reactions (0.1%, 0%).
Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences, with the frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation. There have been occasional postmarketing reports of death by suicide, delusions, psychosis-like behaviour, and catatonia although a causal relationship to the use of efavirenz cannot be determined from these reports.

Nervous system symptoms.

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported side effects in patients receiving Stocrin 600 mg once daily in clinical trials. In controlled clinical trials where 600 mg once daily Stocrin was administered with other antiretroviral agents, 19.4% of patients experienced nervous system symptoms of moderate to severe intensity compared to 9% of patients receiving control regimens. These symptoms were severe in 2.0% of patients receiving Stocrin 600 mg once daily and in 1.3% of patients receiving control regimens. In clinical trials, 2.1% of patients treated with 600 mg of Stocrin discontinued therapy because of nervous system symptoms (see Section 4.4 Special Warnings and Precautions for Use).
Nervous system symptoms usually begin during the first one or two days of therapy and generally resolve after the first 2-4 weeks. In one clinical study, the monthly prevalence of nervous system symptoms of at least moderate severity between weeks 4 and 48 ranged from 5%-9% in patients treated with regimens containing efavirenz and 3%-5% in patients treated with the control regimen. In a study of uninfected volunteers, a representative nervous system symptom had a median time to onset of 1 hour postdose and a median duration of 3 hours. Dosing at bedtime improves the tolerability of these symptoms and is recommended during the first weeks of therapy and in patients who continue to experience these symptoms (see Section 4.2 Dose and Method of Administration). Dose reduction or splitting the daily dose has not been shown to provide benefit and is not recommended.
Drug related clinical adverse experiences of moderate or severe intensity observed in ≥ 2% of patients in three controlled clinical trials are presented in Table 3.
Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected paediatric patients (3 months to 21 years of age) who received Stocrin (efavirenz) in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in paediatric patients (32% for all grades regardless of causality) and more often of higher grade (i.e. more severe). Two (1.1%) paediatric patients experienced grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) paediatric patients had grade 4 rash (all erythema multiforme). Five paediatric patients (2.7%) discontinued from the study because of rash (also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Adverse clinical experiences of moderate to severe intensity observed in less than 2% of patients receiving Stocrin in all phase II/III studies, including the North American expanded access program, and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below by body system.

Body as a whole.

Alcohol intolerance, allergic reaction, asthenia, fever, hot flushes, malaise, influenza-like symptoms, pain, peripheral oedema, syncope.

Central and peripheral nervous system.

Ataxia, appetite increased, confusion, convulsions, impaired coordination, impotence, libido increased, libido decreased, migraine headaches, neuralgia, paraesthesia, peripheral neuropathy, speech disorder, tremor, vertigo.

Gastrointestinal.

Gastritis, gastroenteritis, gastroesophageal reflux, dry mouth, pancreatitis.

Hearing and vestibular.

Tinnitus.

Cardiovascular.

Flushing, palpitations, tachycardia, thrombophlebitis.

Liver and biliary system.

Hepatitis.

Metabolic and nutritional.

Weight gain, weight loss.

Musculoskeletal.

Arthralgia, myalgia.

Psychiatric.

Aggravated depression, agitation, amnesia, anxiety, apathy, emotional lability, euphoria, hallucination, psychosis.

Respiratory.

Asthma, sinusitis, upper respiratory tract infection.

Skin and appendages.

Acne, alopecia, eczema, folliculitis, seborrhoea, skin exfoliation, urticaria.

Special senses.

Abnormal vision, diplopia, parosmia, taste perversion.

Lipodystrophy and metabolic abnormalities.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsovisceral fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hypergylcaemia and hyperlactataemia.

Laboratory test findings.

Laboratory abnormalities.

Liver enzymes.

Elevations of AST and ALT to greater than five times the upper limit of the normal range were seen in 3% of 1008 patients treated with 600 mg of efavirenz. Similar elevations were seen in patients treated with control regimens. In 156 patients treated with 600 mg of efavirenz who were seropositive for hepatitis B and/or C, 7% developed AST levels and 8% developed ALT levels greater than five times the upper limit of the normal range. In 91 patients seropositive for hepatitis B and/or C treated with control regimens, 5% developed AST elevations and 4% developed ALT elevations to those levels. Elevations of GGT to greater than five times the upper limit of the normal range were observed in 4% of all patients treated with 600 mg of efavirenz and in 10% of patients seropositive for hepatitis B or C. In patients treated control regimens, the incidence of GGT elevations to this level was 1.5-2%, irrespective of hepatitis B or C serology. Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity (see Section 4.4 Special Warnings and Precautions for Use).

Lipids.

Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Stocrin. Increases in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed in patients treated with efavirenz + ZDV + 3TC and of approximately 40% and 35% in patients treated with efavirenz + IDV. The effects of efavirenz on triglycerides and LDL were not well characterised. The clinical significance of these findings is unknown (see Section 4.4 Special Warnings and Precautions for Use).

Postmarketing information.

Additional undesirable effects reported in postmarketing surveillance include:

Eye disorders.

Blurred vision.

Gastrointestinal disorders.

Abdominal pain, pancreatitis.

Hepatobiliary disorders.

Hepatic failure.

Nervous system disorders.

Convulsions, cerebellar coordination and balance disturbances, tremor, encephalopathy.

Psychiatric disorders.

Neurosis, paranoid reaction.

Reproductive system and breast disorders.

Gynaecomastia.

Special senses.

Tinnitus.

Skin and subcutaneous tissue disorders.

Pruritus, photoallergic dermatitis, redistribution/ accumulation of body fat in areas such as the back of the neck, breasts, abdomen and retroperitoneum, flushing.
A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.
Cases of autoimmune hepatitis have been reported with the use of medicines containing efavirenz.
Laboratory abnormalities.

Amylase.

Asymptomatic increases in serum amylase levels have been observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.

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

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with Stocrin should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.
Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Stocrin. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase (RT) with respect to template, primer or nucleoside triphosphates, with a small component of competitive inhibition. HIV-2 RT and human cellular DNA polymerases α, β, γ and δ are not inhibited by concentrations of efavirenz well in excess of those achieved clinically.

Pharmacodynamics.

In vitro HIV susceptibility.

The clinical significance of in vitro susceptibility of HIV-1 to efavirenz has not been established. The in vitro antiviral activity of efavirenz was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs) and macrophage/ monocyte cultures enriched from PBMCs. The 90-95% inhibitory concentration (IC90-95) of efavirenz for wild type laboratory adapted strains and clinical isolates ranged from 1.7 to ≤ 25 nanoM. Efavirenz potency against variants with mutations of S48T, V108I, V179D, Y181C, P236L or variants with amino acid substitutions in the protease gene was similar to that seen against wild type. Modest resistance (less than 9-fold) was observed against variants containing the mutations A98G, K101E, V106A, Y188C or G190A. The point mutations which led to the highest apparent resistance to efavirenz inhibition in vitro were L100I (17 to 22-fold resistance) and K103N (18 to 33-fold resistance). The following multiple base pair mutated variants which encode RTs with one or more amino acid substitutions showed increased resistance to efavirenz in vitro with respect to wild type: S48T + G190S (97-fold), Y181C + K103N (133-fold), G190A + K103N (130-fold), Y188L (140 to 500-fold), K101E + K103N (500-fold) and L100I + K103N (> 1000-fold).
Efavirenz demonstrated synergistic activity in cell culture in combination with the nucleoside analogue reverse transcriptase inhibitors (NRTIs) zidovudine (ZDV) or didanosine (ddI), or the protease inhibitor (PI) indinavir.

Cardiac electrophysiology.

The effect of Stocrin on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days (see Section 4.4 Special Warnings and Precautions for Use).

Drug resistance.

The potency of efavirenz in cell culture against viral variants with amino acid substitutions at positions 48, 108, 179, 181 or 236 in RT or variants with amino acid substitutions in the protease was similar to that observed against wild type viral strains. The single substitutions which led to the highest resistance to efavirenz in cell culture correspond to a leucine to isoleucine change at position 100 (L100I, 17 to 22-fold resistance) and a lysine to asparagine at position 103 (K103N, 18 to 33-fold resistance). Greater than 100-fold loss of susceptibility was observed against HIV variants expressing K103N in addition to other amino acid substitutions in RT.
K103N was the most frequently observed RT substitution in viral isolates from patients who experienced a significant rebound in viral load during clinical studies of efavirenz in combination with indinavir or zidovudine + lamivudine. Substitutions at RT positions 98, 100, 101, 108, 138, 188, 190 or 225 were also observed, but at lower frequencies, and often only in combination with K103N. The pattern of amino acid substitutions in RT associated with resistance to efavirenz was independent of the other antiviral medications used in combination with efavirenz.

Cross resistance to other antiviral agents.

Cross resistance profiles for efavirenz, nevirapine and delavirdine in cell culture demonstrated that the K103N substitution confers loss of susceptibility to all three NNRTIs. Two of three delavirdine resistant clinical isolates examined were cross resistant to efavirenz and contained the K103N substitution. A third isolate which carried a substitution at position 236 of RT was not cross resistant to efavirenz.
Viral isolates recovered from PBMCs of patients enrolled in efavirenz clinical trials who showed evidence of treatment failure (viral load rebound) were assessed for susceptibility to NNRTIs. Thirteen isolates previously characterised as efavirenz resistant were also resistant to nevirapine and delavirdine. Five of these NNRTI resistant isolates were found to have K103N or a valine to isoleucine substitution at position 108 (V108I) in RT. Three of the efavirenz treatment failure isolates tested remained sensitive to efavirenz in cell culture and were also sensitive to nevirapine and delavirdine.
The potential for cross resistance between efavirenz and protease inhibitors is low because of the different enzyme targets involved. The potential for cross resistance between efavirenz and NRTIs is low because of the different binding sites on the target and mechanism of action.

Clinical trials.

In the clinical studies described below, the primary efficacy measure was the percent of patients with plasma HIV-RNA < 400 copies/mL, using the Roche RT-PCR (Amplicor) HIV-1 Monitor Assay. Using this assay, which has a lower quantification limit of 400 copies/mL, values obtained which were below the limit of quantification were set as 400 copies/mL for analyses of mean change from baseline. HIV-RNA results are also described using an RT-PCR assay with a lower limit of quantification of 50 copies/mL (Ultrasensitive).
In the noncompleter equals failure analyses (NC = F) presented in Figures 1 and 2, patients that terminated the study early for any reason or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification (> 400 copies/mL) were considered treatment failures. In the observed data analyses, presented in Tables 4 and 5, patients on treatment with HIV-RNA > 400 copies/mL at the specified time point are considered treatment failures.

Study 006: Stocrin (efavirenz) + indinavir or Stocrin + zidovudine + lamivudine versus indinavir + zidovudine + lamivudine in antiretroviral naive or NRTI experienced (lamivudine naive) patients.

Study 006 was a randomised, open label trial to evaluate the plasma HIV-RNA suppression achieved by Stocrin in combination with either indinavir (IDV) or with zidovudine (ZDV) + lamivudine (3TC) compared to indinavir plus zidovudine + lamivudine in HIV infected patients naive to lamivudine, protease inhibitors and NNRTIs. Patients were randomised to one of three treatment regimens: Stocrin (600 mg once daily) + indinavir (1000 mg every 8 hours) or Stocrin (600 mg once daily) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h) versus indinavir (800 mg every 8 hours) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Forty-eight week data analyses are presented for 614 patients (mean age 36.3 years (range 18-64), 58% Caucasian, 86% male). Mean baseline CD4 cell count was 342 cells/mm3, and mean baseline HIV-RNA plasma level was 4.76 log10 copies/mL. The NC = F analysis of the percent of patients achieving plasma HIV-RNA levels < 400 copies/mL is presented in Figure 1. Other efficacy results are summarised in Table 4.

Study 020: Protease inhibitor + two NRTIs with/ without Stocrin in NRTI experienced patients.

Study 020 was a randomised, double blind, placebo controlled study in NRTI experienced, protease inhibitor and NNRTI naive patients designed to compare quadruple therapy consisting of Stocrin + indinavir + 2 nucleoside analogue reverse transcriptase inhibitors versus triple therapy consisting of indinavir + 2 NRTIs after 24 weeks of treatment. Patients were randomised to receive either Stocrin (600 mg once daily) + indinavir (1000 mg every 8 hours) + 2 NRTIs or indinavir (800 mg every 8 hours) + 2 NRTIs. Sixty-nine percent of the 327 patients (mean age 38.5 years [range 20-69], 52% Caucasian, 83% male) changed their NRTI regimen at study initiation. Mean baseline CD4 cell count was 328 cells/mm3, and mean baseline HIV-RNA plasma level was 4.41 log10 copies/mL. The NC = F analysis of the percent of patients achieving plasma HIV-RNA levels < 400 copies/mL at 24 weeks is presented in Figure 2. Other efficacy results are summarised in Table 5.

Study ACTG 364: Stocrin in combination with nelfinavir in NRTI experienced patients.

ACTG 364 was a 48 week double blind, placebo controlled study in NRTI experienced patients, but NNRTI and protease inhibitor naive, who had completed two prior ACTG studies. One hundred and ninety-six HIV infected patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male) received NRTIs in combination with Stocrin (600 mg QD), or nelfinavir (NFV, 750 mg TID), or Stocrin (600 mg QD) + nelfinavir in a randomised double blinded manner. Upon entry into the study, all patients were assigned a new open label NRTI regimen, which was dependent on their previous NRTI treatment experience. Overall efficacy results are summarised in Table 6.

Use in children.

Study AI266922 was an open label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Stocrin in combination with didanosine and emtricitabine in antiretroviral naive and -experienced paediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with Stocrin. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 132 weeks; 27% of patients discontinued before week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 215 cells/mm3 and the median increase in CD4+ percentage was 6%.
Study PACTG 1021 was an open label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Stocrin in combination with didanosine and emtricitabine in paediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with Stocrin. At baseline, median plasma HIV 1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in CD4+ percentage was 13%. In paediatric population < 3 years of age the proportions of subjects with viral load suppressed to < 400 and < 50 c/mL were 50% and 50%, respectively.
Study PACTG 382 was an open label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Stocrin in combination with nelfinavir and an NRTI in antiretroviral naïve and NRTI experienced paediatric patients. One hundred and two patients 3 months to 16 years of age (median 5.7 years) were treated with Stocrin. Eighty seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%. In paediatric population < 2 years, the proportions of subjects with viral load suppressed to < 400 and < 50 c/mL were 38% and 15%, respectively.

5.2 Pharmacokinetic Properties

Absorption.

Peak efavirenz plasma concentrations of 1.6-9.1 microM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. Time to peak plasma concentrations (3-5 hours) did not change following multiple dosing and steady-state plasma concentrations were reached in 6-7 days.
In HIV infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were linear with 200 mg, 400 mg, and 600 mg daily doses. In 35 patients receiving Stocrin 600 mg once daily, steady-state Cmax was 12.9 microM, steady-state Cmin was 5.6 microM, and AUC was 184 microM.hour.
Effect of food on oral absorption.

Capsules.

Administration of a single 600 mg dose of efavirenz capsules with a high fat/ high caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced fat/ normal caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions (see Section 4.2 Dose and Method of Administration).

Tablets.

Administration of a single 600 mg efavirenz tablet with a high fat/ high caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions (see Section 4.2 Dose and Method of Administration).

Distribution.

Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n = 9) who received Stocrin 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the nonprotein bound (free) fraction of efavirenz in plasma.

Metabolism.

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. In vitro studies have shown that efavirenz inhibited P450 isozymes 2C9, 2C19 and 3A4 with Ki values (8.5-17 microM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 microM) only at concentrations well above those achieved clinically.
Efavirenz plasma exposure may be increased in patients with the homozygous G516T genetic variant of the CYP2B6 isoenzyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz associated adverse events cannot be excluded.
Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours). The degree of CYP3A4 induction is expected to be similar between a 400 mg and 600 mg dose of efavirenz based on pharmacokinetic interaction studies in which daily 400 mg or 600 mg efavirenz doses in combination with indinavir did not appear to cause any further reduction of indinavir AUC compared to a 200 mg dose of efavirenz.

Excretion.

Efavirenz has a relatively long terminal half-life of 52 to 76 hours after single doses and 40-55 hours after multiple doses. Approximately 14-34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.

Characteristics in patients.

Hepatic impairment.

Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience in patients with chronic liver disease, caution should be exercised in administering Stocrin to patients with liver disease (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.

Gender and race.

Pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.

Geriatric use.

Clinical studies of Stocrin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Paediatric use.

The pharmacokinetics of efavirenz in paediatric patients aged ≥ 3 years were similar to adults.
For paediatric patients aged ≥ 3 years, dosage was calculated on the basis of body size to be equivalent to an adult 600 mg capsule dose, and subsequently further adjusted based on serum concentration in the first two weeks of dosing.
The study therapy may be discontinued for failure to achieve an efavirenz AUC of at least 110 microM.h despite multiple efavirenz dose adjustment/ formulation changes.

5.3 Preclinical Safety Data

Genotoxicity.

Efavirenz was not genotoxic in assays for gene mutations (S. typhimurium, E. coli and Chinese hamster ovary cells) and chromosomal damage (human peripheral blood lymphocytes, Chinese hamster ovary cells, and a mouse micronucleus assay).

Carcinogenicity.

Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150 or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumour incidence above background were seen in males. There was no NOAEL in females established for this study because tumour findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study no increases in tumour incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following inactive ingredients: croscarmellose sodium, cellulose microcrystalline, sodium lauryl sulfate, hyprolose, lactose monohydrate and magnesium stearate.
The film coating contains the following inactive ingredients and dyes: hypromellose, titanium dioxide, macrogol 400 and carnauba wax. In addition, the 50 mg, 200 mg and 600 mg tablets contain iron oxide yellow CI 77492. The 300 mg tablets are printed with purple ink, Opacode WB NS-78-10013-N [ARTG no. 4603]. The 50 mg, 200 mg and 600 mg tablets are not printed with ink.

6.2 Incompatibilities

Not applicable.

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.

6.5 Nature and Contents of Container

Stocrin 50 mg.

HDPE bottle containing 30* tablets.

Stocrin 200 mg.

HDPE bottles containing 90 tablets.

Stocrin 300 mg.

HDPE bottles containing 60* tablets.

Stocrin 600 mg.

HDPE bottles containing 30 tablets.
*These strengths and/or pack sizes are not currently available in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Efavirenz is chemically described as (S)-6-chloro-4- (cyclopropylethynyl)-1,4 -dihydro-4-(trifluoromethyl) -2H-3,1-benzoxazin-2-one.
Its empirical formula is C14H9ClF3NO2. and its structural formula is:

CAS number.

154598-52-4.
Efavirenz has a molecular mass of 315.68. It is practically insoluble in water (< 10 microgram/mL).

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine Schedule 4 (S4).

Summary Table of Changes