Consumer medicine information

Isentress and Isentress HD

Raltegravir

BRAND INFORMATION

Brand name

Isentress, Isentress HD

Active ingredient

Raltegravir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Isentress and Isentress HD.

SUMMARY CMI

ISENTRESS and ISENTRESS HD®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking Isentress?

ISENTRESS contains the active ingredient raltegravir. ISENTRESS is used in combination with other anti-HIV medicines to treat adults, adolescents, and children 2 years of age and older who are infected with HIV.

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

2. What should I know before I take Isentress?

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

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

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

3. What if I am taking other medicines?

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

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

4. How do I take ISENTRESS?

Adults: Take one ISENTRESS 400mg tablet twice daily or two ISENTRESS HD 600mg once daily as directed by your doctor or pharmacist. Swallow whole.

Children and Adolescents: Your child's doctor will tell you how many tablets your child should take and the type of ISENTRESS (ISENTRESS or ISENTRESS HD tablet or ISENTRESS chewable table) based on your child's age and weight.

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

5. What should I know while taking ISENTRESS?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ISENTRESS.
  • Do not change your dose or stop taking ISENTRESS or your other HIV medicines without first talking with your doctor
Things you should not do
  • Do not stop taking your medicine or lower the dosage without checking with your doctor. The amount of virus in your blood may increase if the medicine is stopped for even a short period of time. HIV may develop resistance to ISENTRESS and become harder to treat
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ISENTRESS affects you.
  • There have been side effects reported with ISENTRESS that may affect your ability to drive or operate machinery.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 30°C and where children cannot reach them
  • Keep your tablets in the bottle until it is time to take them, if you take the tablets out of the bottle they may not keep well

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

6. Are there any side effects?

The most common side effects are nausea, headache, diarrhoea, tiredness, inflammation of the nasal passages and throat, trouble sleeping, upper respiratory tract infection, cough, fever, bronchitis, back pain and depression.

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: any severe skin reaction, hives or nettlerash, fainting, fast or irregular heart beat or tightness in the chest.

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

ISENTRESS and ISENTRESS HD®

Active ingredient: raltegravir

Consumer Medicine Information (CMI)

This leaflet provides important information about using ISENTRESS. 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 ISENTRESS

Where to find information in this leaflet:

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

1. Why am I taking ISENTRESS?

ISENTRESS contains the active ingredient raltegravir.

ISENTRESS is used in combination with other anti-HIV medicines to treat adults, adolescents, and children 2 years of age and older who are infected with HIV. The children and adolescents (2 - 18 years of age) who participated in the ISENTRESS studies had previously taken HIV medicines.

ISENTRESS belongs to a group of medicines called integrase inhibitors. It works by blocking HIV integrase, one of the enzymes that is needed during the replication process for HIV to make more virus. When integrase is blocked by ISENTRESS, the virus is not able to reproduce normally. This helps reduce the amount of virus in the blood.

When used with other anti-HIV medicines, ISENTRESS helps reduce the amount of HIV virus in your blood (called "viral load") and increase the number of CD4 (T) cells (Immune Cells that help fight infection). Reducing the amount of HIV in the blood may keep your immune system healthy, so it can help fight infection.

ISENTRESS may not have these effects in all patients.

ISENTRESS does not cure HIV infection or AIDS.

It is very important that you stay under the care of your doctor during treatment with ISENTRESS.

2. What should I know before I take ISENTRESS?

Warnings

Do not use ISENTRESS if:

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

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • have or have had any allergies to any other medicines, foods, preservatives or dyes
  • are not sure whether you should start taking this medicine.

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?

Phenylketonuria

Tell your doctor if you have phenylketonuria.

ISENTRESS chewable tablets contain aspartame, a source of phenylalanine, which may be harmful to people with phenylketonuria.

Pregnancy

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

You should not take ISENTRESS when you are pregnant unless your doctor says you should. Your doctor will discuss the risks and benefits of using ISENTRESS 400 mg twice daily if you are pregnant.

There are limited data on the use of ISENTRESS HD 1200 mg (2 x 600 mg) once daily in pregnant women

Breastfeeding

Do not breast-feed if you are taking this medicine.

It is recommended that HIV-infected women should not breast-feed their infants because of the possibility that your baby can be infected with HIV through your breast milk. Talk with your doctor about the best way to feed your baby.

Child under the age of 2 years

Do not give this medicine to a child under the age of 2 years. ISENTRESS has not been studied in children under the age of 2.

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.

ISENTRESS can be taken with most medicines, however some medicines are not recommended with ISENTRESS. Some medicines may interfere with ISENTRESS and affect how it works.

Medicines that may increase the effect of ISENTRESS include:

  • Atazanavir, for treatment of HIV

Medicines that may reduce the effect of ISENTRESS include:

  • Antacids
  • Rifampin, a medicine used to treat tuberculosis
  • Tipranavir/Ritonavir, for treatment of HIV
  • Phenytoin and Phenobarbitone, medicines used to treat seizures

These medicines may affect how well ISENTRESS works. You may need different amounts of your medicines, or you may need to take different medicines.

Keep a list of all your medicines and to show your doctor or pharmacist.

Do not start taking a new medicine without telling your doctor or pharmacist. They can tell you if it is safe to take ISENTRESS with other medicines.

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

4. How do I take ISENTRESS?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

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

How much to take

Adults

  • Take one ISENTRESS 400mg tablet twice daily or two ISENTRESS HD 600mg once daily as directed by your doctor or pharmacist. Swallow whole

Children and Adolescents

  • Your child's doctor will tell you how many tablets your child should take and the type of ISENTRESS (ISENTRESS or ISENTRESS HD tablet or ISENTRESS chewable table) based on your child's age and weight
  • The 100mg chewable tablet is scored and can be split into equal halves.

Do not take more than 300mg of the chewable tablet twice a day.

Chewable tablets are to be chewed, not swallowed whole.

Do not switch between the 400mg or 600mg tablet and the chewable tablet.

When to take ISENTRESS

  • ISENTRESS should be used at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It is very important to take each of your anti-HIV medicines as prescribed and at the right times of day. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV (drug resistance).

How to take ISENTRESS

  • Take ISENTRESS as directed by mouth, with or without food.
  • ISENTRESS must be used with other anti-HIV medicines
  • If taking iron salts (to treat and prevent iron deficiency or anaemia): You should wait at least two hours between taking iron salts and taking ISENTRESS, as these medicines may reduce ISENTRESS efficacy.

How long to take ISENTRESS

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Do not change your dose or stop taking ISENTRESS or your other HIV medicines without first talking with your doctor.

When your supply of ISENTRESS starts to run low, get more from your doctor or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short period of time. HIV may develop resistance to ISENTRESS and become harder to treat.

If you forget to take ISENTRESS

If you miss your dose at the usual time, take it as soon as you remember.

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

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

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much ISENTRESS

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

You should immediately:

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

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

5. What should I know while taking ISENTRESS?

Things you should do

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

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

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

Starting antiretroviral treatment

In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from opportunistic infections (eg: pneumonia, tuberculosis or a painful blistering rash known as shingles) may occur when combination antiretroviral treatment is started.

Call your doctor straight away if you:

  • notice any symptoms of infection

Tell and remind any doctor, dentist, pharmacist or other health professional you visit that you are using ISENTRESS.

Things you should not do

Do not stop taking your medicine or lower the dosage without checking with your doctor.

The amount of virus in your blood may increase if the medicine is stopped for even a short period of time. HIV may develop resistance to ISENTRESS and become harder to treat.

Driving or using machines

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

There have been side effects reported with ISENTRESS that may affect your ability to drive or operate machinery. Individual responses to ISENTRESS may vary.

Looking after your medicine

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Keep this leaflet with the medicine, you may need to read it again.

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

If you take the tablets out of the pack/bottle they may not keep well.

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

Keep your tablets in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C; for example, do not store it:

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

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines

Getting rid of any unwanted medicine

If your doctor tells you to stop taking this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Your doctor will discuss these with you and will explain the risks and benefits of your treatment. Less serious side effects

Less serious side effectsWhat to do
The most common side effects are:
  • Nausea
  • Headache
  • Diarrhoea
  • Tiredness
  • Inflammation of the nasal passages and throat
  • Trouble sleeping
  • Upper respiratory tract infection
  • Cough
  • Fever
  • Bronchitis
  • Back pain
  • Depression
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Hypersensitivity reaction
  • Severe skin reactions
  • Pinkish, itchy swellings on the skin, also called hives or nettlerash
  • Tiredness, headaches, being short of breath when exercising, dizziness and looking pale.
  • Frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • Abdominal pain, nausea, vomiting, vomiting blood and blood in the bowel motions
  • Loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
  • That you are bleeding or bruising more easily than normal
  • Aching muscles, muscle tenderness or weakness, not caused by exercise. (On rare occasions, muscle problems can be serious, including muscle breakdown resulting in kidney damage.)
  • Fainting
  • Fast or irregular heartbeat
  • Wheeziness due to tightness in the chest
Since the medicine has been on the market the following side effects have been reported:
  • Depression
  • Suicidal thoughts and actions
  • Low Blood platelet count
  • Muscle tenderness or weakness
  • Clumsiness and lack of coordination
  • Rash with or without increase in some white blood cells
  • Liver Failure
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.

Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell, or if any known side effect does not go away or gets worse.

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

The long-term effects of ISENTRESS are unknown at this time. Tell your doctor if you notice any other effects.

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 ISENTRESS 400 mg Tablet contains

Active ingredient
(main ingredient)		Raltegravir 400 mg
Other ingredients
(inactive ingredients)		Microcrystalline cellulose
Lactose monohydrate
Calcium phosphate dibasic anhydrous
Hypromellose 2208
Poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant)
Sodium stearyl fumarate
Magnesium stearate.
The pink film coating contains the following inactive ingredients:
Polyvinyl alcohol
Titanium dioxide
Polyethylene glycol 3350
Talc
Iron oxide red
Iron oxide black

What ISENTRESS HD 600 mg Tablet contains

Active ingredient
(main ingredient)		Raltegravir 600 mg
Other ingredients
(inactive ingredients)		Hypromellose 2910
Croscarmellose sodium
Microcrystalline cellulose
Magnesium stearate
Carnauba wax
The yellow film coating contains the following inactive ingredients:
Lactose monohydrate
Hypromellose 2910
Titanium dioxide
Glycerol triacetate
Iron oxide yellow
Iron oxide black

What ISENTRESS 25 mg and 100 mg Chewable Tablets contains

Active ingredient
(main ingredient)		Raltegravir 25 mg and 100 mg
Other ingredients
(inactive ingredients)		Hydroxypropylcellulose
Sucralose
Saccharin sodium
Sodium citrate
Mannitol
Iron oxide red CI77411 (100 mg tablet only)
Iron oxide yellow CI77492
Ammonium glycyrrhizinate
Sorbitol
Fructose
Natural and artificial flavours (orange, banana and masking that contains aspartame)
Crospovidone
Magnesium stearate
Sodium stearyl fumarate
Ethylcellulose 20cP
Ammonium hydroxide
Medium chain triglycerides
Oleic acid
Hypromellose 2910/6cp
Macrogol 400

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

ISENTRESS tablets do not contain sucrose, gluten, tartrazine or any other azo dyes.

ISENTRESS 25 mg and 100 mg chewable tablets are banana-orange flavoured.

ISENTRESS chewable tablets contain phenylalanine as part of the artificial sweetener, aspartame. The artificial sweetener may be harmful to people with phenylketonuria.

The chewable tablets do not contain sucrose, gluten, tartrazine or any other azo dyes.

What ISENTRESS looks like

ISENTRESS is available as a 400mg tablet and as a chewable tablet formulation in 100 mg (scored) and 25mg strengths. ISENTRESS HD is available as a 600 mg tablet.

ISENTRESS HD 600 mg (AUST R 280294) is yellow, oval shaped tablet with the corporate logo and "242" on one side and plain on the other. Available in bottles containing 60 tablets

ISENTRESS 400 mg (AUST R 140238) is pink, oval shaped tablet with "227" on one side and plain on the other. Available in bottles containing 60 tablets

ISENTRESS Chewable tablet 25 mg (AUST R 193383) is pale yellow round tablet with the corporate logo on one side and "473" on the other side. Available in bottles containing 60 chewable tablets

ISENTRESS Chewable tablet 100 mg (AUST R 193388) is pale orange oval tablet scored on both sides; one side is plain, and the other side is imprinted with the corporate logo and "477" on either side of the score. Available in bottles containing 60 chewable tablets.

Who distributes ISENTRESS

ISENTRESS is supplied in Australia by:

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

This leaflet was prepared in November 2023.

WRM-WPPI-MK0518-MF-042023WPPI-MK0518-MF-032023

RCN000025612, 000025862

Copyright © 2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Isentress, Isentress HD

Active ingredient

Raltegravir

Schedule

S4

 

1 Name of Medicine

Isentress (raltegravir) 400 mg tablet, 25 mg chewable tablet and 100 mg chewable tablet.
Isentress HD (raltegravir) 600 mg tablet.

2 Qualitative and Quantitative Composition

Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol. The pKa is 6.6 in water. The octanol/water partition at pH 7.4 is 2.80.

Isentress HD 600 mg tablet.

Each film-coated tablet of Isentress HD contains 600 mg of raltegravir (as potassium salt).

Isentress 400 mg tablet.

Each film-coated tablet of Isentress contains 400 mg of raltegravir (as potassium salt).

Isentress 100 mg chewable tablet.

Each chewable tablet contains 100 mg of raltegravir (as potassium salt).

Isentress 25 mg chewable tablet.

Each chewable tablet contains 25 mg of raltegravir (as potassium salt).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

4 Clinical Particulars

4.1 Therapeutic Indications

Isentress or Isentress HD, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults, adolescents and children from the age of 2 years.
This indication is based on analyses of plasma HIV-1 RNA levels in controlled studies of Isentress (see Section 5.1).
The indication in paediatric patients is based on the evaluation of safety, tolerability, pharmacokinetic parameters and efficacy of Isentress through at least 24 weeks in a multicentre, open label, non-comparative study in HIV-1 infected, treatment experienced children and adolescents 2 to 18 years of age.
The use of other active antiretroviral agents in combination with Isentress is associated with a greater likelihood of treatment response (see Section 5.1).
There are no study results demonstrating the effect of Isentress on clinical progression of HIV-1 infection.

4.2 Dose and Method of Administration

Isentress or Isentress HD is to be given in a combination regimen with other antiretroviral agents.
Isentress or Isentress HD can be administered with or without food.
Isentress is available in the following dose strengths:
400 mg film-coated tablet for twice daily use;
chewable tablet in 100 mg (scored) and 25 mg strengths for twice daily use.
Isentress HD is available in the following dose strength:
600 mg film-coated tablet for once daily use.
The formulations have different pharmacokinetic profiles, therefore do not substitute the 400 mg tablet for the 600 mg tablet to create a 1200 mg once daily dose. Do not substitute the chewable tablet for the 400 mg or 600 mg tablet.
It is not recommended to chew, crush or split the 400 mg tablet or 600 mg tablet.
Chewable tablets are to be chewed, not swallowed whole.
The maximum dose of chewable tablets is 300 mg twice daily.
For the treatment of patients with HIV-1 infection, the dosage of Isentress or Isentress HD is as follows:

Adults.

See Table 1.

Paediatric patients.

If at least 40 kg in weight and either treatment naive or virologically suppressed on an initial regimen of Isentress 400 mg twice daily. Isentress HD 1200 mg (2 x 600 mg) once daily, or;
Isentress 400 mg twice daily, or;
Isentress 300 mg chewable tablets twice daily.

Note.

Do not substitute the 400 mg tablet for the 600 mg tablet to create a 1200 mg once daily dose.
If at least 25 kg in weight. One Isentress 400 mg tablet twice daily, orally, or;
weight based dosing for chewable tablets as specified in Table 2.
If between 7 and 25 kg in weight. Weight based dosing for chewable tablets as specified in Table 2.

Renal insufficiency.

There were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy participants. No dosage adjustment is necessary. Because the extent to which Isentress or Isentress HD may be dialyzable is unknown, dosing before a dialysis session should be avoided.

Hepatic insufficiency.

There were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy participants. No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied.

4.3 Contraindications

Isentress or Isentress HD is contraindicated in patients who are hypersensitive to any component of this medicine.

4.4 Special Warnings and Precautions for Use

Severe skin and hypersensitivity reactions.

Severe, potentially life threatening, and fatal skin reactions have been reported in patients taking Isentress or Isentress HD concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterised by rash, constitutional findings and, sometimes, organ dysfunction, including hepatic failure. Discontinue Isentress or Isentress HD and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping Isentress or Isentress HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Drug interactions.

Antacids.

Coadministration of Isentress 400 mg twice daily with aluminium and magnesium antacids resulted in reduced raltegravir plasma levels. Coadministration of Isentress 400 mg twice daily with aluminium and/or magnesium antacids is not recommended (see Section 4.5).
Coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily with calcium carbonate and aluminium/magnesium containing antacids resulted in reduced raltegravir plasma levels therefore coadministration is not recommended.

Atazanavir.

Coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily with atazanavir resulted in increased raltegravir plasma levels therefore coadministration is not recommended (see Section 4.5).

Iron salts.

Given simultaneously iron salts may reduce raltegravir plasma levels; taking iron salts at least two hours from the administration of raltegravir may limit this effect.

Tipranavir/ritonavir.

Coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily with tipranavir/ritonavir could result in decreased raltegravir trough plasma levels therefore coadministration is not recommended (see Section 4.5).

Strong inducers of drug metabolising enzymes.

Caution should be used when coadministering Isentress 400 mg twice daily with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g. rifampin) due to reduced plasma concentrations of raltegravir (see Section 4.5).
Strong inducers of drug metabolising enzymes (e.g. rifampin) have not been studied with Isentress HD 1200 mg (2 x 600 mg) once daily but could result in decreased raltegravir trough plasma level therefore coadministration with Isentress HD 1200 mg (2 x 600 mg) once daily is not recommended.

Immune reconstitution syndrome.

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease) 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.

Paediatric use.

IMPAACT (P1066) was conducted in treatment-experienced HIV infected children and adolescents aged 2 to 18 years of age. Given raltegravir exposures in children approximated that in adults, it is expected the safety and efficacy profile in treatment-naive HIV infected children aged 2 to 18 years would not be substantially different from that seen in treatment-naive adults.
Isentress HD 1200 mg (2 x 600 mg) once daily has not been studied in paediatric patients. However, population PK modeling and simulation support the use of 1200 mg (2 x 600 mg) once daily in paediatric patients weighing at least 40 kg (see Section 5.2).
Safety and effectiveness of Isentress or Isentress HD in children under 2 years of age have not been established.

Juvenile development.

Oral administration of up to 600 mg/kg/day to juvenile rats resulted in drug irritation effects in the stomach which were similar to those seen in adult rats. The drug exposure (AUC) with this dose was approximately 1.5-fold the human value at the recommended dose of 400 mg twice daily. No additional toxicities were noted in juvenile rats and development to maturity was unaffected by treatment.

Use in the elderly.

Clinical studies of Isentress did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Use in hepatic impairment.

The safety and efficacy of Isentress have not been established in patients with severe underlying liver disorders.

Phenylketonurics.

Chewable tablets contain phenylalanine as a component of aspartame. Each 25 mg chewable tablet contains approximately 0.05 mg phenylalanine. Each 100 mg chewable tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Effects on laboratory tests.

See Section 4.8, Laboratory abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of raltegravir on the pharmacokinetics of other agents.

Raltegravir does not inhibit (IC50 > 100 microM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolised by CYP3A4 in vivo by demonstrating a lack of meaningful effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate.
Similarly, raltegravir is not an inhibitor (IC50 > 50 microM) of the UDP-glucuronosyltransferases (UGTs) tested (UGT1A1, UGT2B7) and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, Isentress is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g. protease inhibitors, NNRTIs, methadone, opioid analgaesics, statins, azole antifungals, proton pump inhibitors, oral contraceptives and anti-erectile dysfunction agents).
In drug interaction studies performed using the 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, maraviroc, tenofovir disoproxil fumarate, midazolam, lamivudine, etravirine, darunavir/ritonavir and boceprevir. In a multiple-dose drug interaction study, ethinyl estradiol and norelgestromin AUC values were 98% and 114%, respectively, when coadministered with raltegravir as compared to when administered without raltegravir. In a multiple-dose drug interaction study, tenofovir AUC and trough concentrations when coadministered with raltegravir were 90% and 87% of values obtained with tenofovir disoproxil fumarate monotherapy. In another drug interaction study, midazolam AUC from coadministration was 92% of the value obtained with midazolam alone. In a Phase II study, lamivudine pharmacokinetics were similar in patients receiving combinations with raltegravir versus with efavirenz. Findings from clinical studies conducted for Isentress 400 mg twice daily to evaluate the effect of raltegravir on coadministered drugs and presented in Table 3 can be extended to raltegravir 1200 mg once daily, unless otherwise noted.

Effect of other agents on the pharmacokinetics of raltegravir.

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes.
Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Inducers of drug metabolising enzymes.

Coadministration of Isentress 400 mg twice daily with drugs that are potent inducers of UGT1A1, such as rifampin (an inducer of numerous drug metabolising enzymes), reduces plasma concentrations of raltegravir. Caution should be used when coadministering Isentress 400 mg twice daily with rifampin or other strong inducers of UGT1A1 (see Section 4.4). If coadministration with rifampin is unavoidable, a doubling of the dose of Isentress can be considered. Until further pharmacokinetic data are available, rifampin coadministration with Isentress chewable tablet is not recommended. The impact of other potent inducers of drug metabolising enzymes, such as phenytoin and phenobarbitone, on UGT1A1 is unknown. Other less potent inducers (e.g. efavirenz, etravirine, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of Isentress 400 mg twice daily.
The impact of drugs that are strong inducers of UGT1A1 such as rifampin on Isentress HD 1200 mg (2 x 600 mg) once daily is unknown, but co-administration is likely to decrease raltegravir trough levels based on the reduction in trough concentrations observed with Isentress 400 mg twice daily; therefore coadministration with Isentress HD 1200 mg (2 x 600 mg) once daily is not recommended. The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown therefore coadministration with Isentress HD 1200 mg (2 x 600 mg) once daily is not recommended. In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of Isentress HD 1200 mg (2 x 600 mg) once daily, therefore other less potent inducers (e.g. efavirenz, nevirapine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with Isentress HD 1200 mg (2 x 600 mg) once daily.

Inhibitors of UGT1A1.

Coadministration of Isentress 400 mg twice daily with drugs that are known to be potent UGT1A1 inhibitors (e.g. atazanavir) increases plasma levels of raltegravir. However, the degree of increase is modest and combination therapy with these inhibitors was well tolerated in the clinical studies such that no dose adjustment is required for Isentress 400 mg twice daily.
Coadministration of atazanavir with Isentress HD 1200 mg (2 x 600 mg) once daily significantly increased plasma levels of raltegravir therefore coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily and atazanavir is not recommended.

Antacids.

Coadministration of Isentress 400 mg twice daily with antacids containing divalent metal cations may reduce raltegravir absorption by chelation, resulting in a decrease of raltegravir plasma levels. Taking an aluminium and magnesium antacid within 6 hours of Isentress administration significantly decreased raltegravir plasma levels. Therefore, coadministration of Isentress 400 mg twice daily with aluminium and/or magnesium containing antacids is not recommended. Coadministration of Isentress 400 mg twice daily with a calcium carbonate antacid decreased raltegravir plasma levels; however, this interaction is not considered clinically meaningful. Therefore, when Isentress 400 mg twice daily is coadministered with calcium carbonate containing antacids, no dose adjustment is recommended.
Coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily with aluminium/magnesium and calcium carbonate containing antacids are likely to result in clinically meaningful reductions in the plasma trough levels of raltegravir. Based on these findings, coadministration of aluminium/magnesium and calcium carbonate containing antacids with Isentress HD 1200 mg (2 x 600 mg) once daily, is not recommended.

Iron salts.

Given simultaneously iron salts may reduce raltegravir plasma levels; taking iron salts at least two hours from the administration of raltegravir may limit this effect.

Agents that increase gastric pH.

Coadministration of Isentress 400 mg twice daily with drugs that are known to increase gastric pH (e.g. omeprazole) may increase raltegravir plasma levels based on increased solubility of Isentress at higher pH. In subjects who received Isentress 400 mg twice daily in combination with proton pump inhibitors (PPIs) or H2 blockers in Protocols 018 and 019, comparable safety profiles were observed in this subgroup relative to subjects not receiving proton pump inhibitors or H2 blockers. Based on these data, proton pump inhibitors and H2 blockers may be coadministered with Isentress 400 mg twice daily without dose adjustment.
Population pharmacokinetic analysis from ONCEMRK (Protocol 292) showed that co-administration of Isentress HD 1200 mg (2 x 600 mg) once daily with PPIs or H2 blockers did not result in statistically significant changes in the pharmacokinetics of raltegravir. Comparable efficacy and safety results were obtained in the absence or presence of these gastric pH-altering agents. Based on these data, proton pump inhibitors and H2 blockers may be coadministered with Isentress HD 1200 mg (2 x 600 mg) once daily.

Additional considerations.

In drug interaction studies of Isentress 400 mg twice daily, atazanavir, efavirenz, ritonavir, tenofovir, and tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of raltegravir. Rifampin, which is a strong inducer of drug metabolising enzymes, caused a decrease in trough levels of raltegravir (see subsections Inducers of drug metabolising enzymes and Inhibitors of UGT1A1 above).
No studies have been conducted to evaluate the drug interactions of ritonavir, tipranavir/ritonavir, boceprevir or etravirine with Isentress HD 1200 mg (2 x 600 mg) once daily. While the magnitudes of change on raltegravir exposure from Isentress 400 mg twice daily by ritonavir, boceprevir or etravirine were small, the impact from tipranavir/ritonavir was greater (GMR Ctrough=0.45, GMR AUC=0.76). Coadministration of Isentress HD 1200 mg (2 x 600 mg) once daily and tipranavir/ritonavir is not recommended.
Previous studies of Isentress 400 mg twice daily showed that coadministration of tenofovir disoproxil fumarate (a component of Truvada) increased raltegravir exposure. Truvada was identified to increase raltegravir 1200 mg (2 x 600 mg) once daily bioavailability by 12%, however its impact is not clinically meaningful. Therefore, coadministration of Truvada and Isentress HD 1200 mg (2 x 600 mg) once daily is permitted.
All interaction studies were performed in adults. Drug interactions are further described in Table 3.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in a 3-fold higher drug exposure (based on AUC) than the human value with the recommended human dose.
(Category A - 400 mg only, B3 for all other strengths)
The pregnancy classification of A only applies to the 2 x 400 mg dose regimen. There are no adequate and well-controlled studies in pregnant women. As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterize the safety for the fetus.

Antiretroviral pregnancy registry.

The Antiretroviral Pregnancy Registry (APR) is an international, voluntary, prospective, exposure-registration, observational study that was established to detect major teratogenic effects resulting from the exposure of pregnant women to antiretroviral therapy.

Risk summary.

Available prospective data from ~ 2700 exposures to raltegravir 400 mg twice daily during pregnancy (including ~ 1000 first trimester exposures) show no difference in the rates of miscarriage, fetal death/stillbirth or congenital defects (including neural tube defects) compared to background rates in the general population (see Human data).

Human data.

Prospective reports of 1166 exposures to raltegravir during pregnancy resulting in 1096 live births are available from the antiretroviral pregnancy registry (APR) (870 reports), clinical trials, and postmarketing data. These reports include 586 first trimester exposures (386 exposures in the periconception period). Overall, the rates of spontaneous abortion and fetal death/stillbirths following exposure to raltegravir were 3.5% (95% CI: 2.5% to 4.7%) and 1.0% (95% CI: 0.5% to 1.7%), respectively. The background rates of spontaneous abortion and fetal death/stillbirth in the US general population are 15-20% and ~ 3%, respectively. The rate of congenital defects was 2.3% (95% CI: 1.2% to 4.0%) following first trimester exposure to raltegravir and 4.2% (95% CI: 2.7% to 6.2%) following second or third trimester exposure to raltegravir. The background birth defect rate is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
Additional prospective data have been reported from two European cohorts, including 1578 exposures to raltegravir during pregnancy (440 exposures in the periconception period). There was no increase in the rate of congenital defect compared to the background rate of 2.5% in the EU population as reported by the European network of population-based registries.
Combining all prospective data, the rate of neural tube defects following raltegravir exposure was not increased compared to the background rate in the general population (there were no reports of neural tube defects among live births following ~ 800 exposures to raltegravir in the periconception period). The estimated world-wide rate of neural tube defects is 0.09%-0.16%.
Isentress 400 mg twice daily can be used during pregnancy, if clinically needed. Existing postmarketing data suggest that tolerability and safety of Isentress 400 mg twice daily in pregnant women is consistent with that observed in other populations.
There are limited data on the use of Isentress HD 1200 mg (2 x 600 mg) once daily in pregnant women.
There are limited data with other doses.

Animal data.

Developmental toxicity studies were conducted in rats and rabbits using oral doses of 600 and 1000 mg/kg/day, respectively. The highest doses in these studies produced systemic exposures in these species approximately 3 to 4-fold above the exposure at the recommended human dose. An increased incidence of fetal supernumerary ribs was observed in rats at the highest dose of 600 mg/kg/day (exposures [adjusted for protein binding] 4.4-fold above the exposure at the recommended human dose), but not at a dose of 300 mg/kg/day (drug exposure [adjusted for protein binding] approximately 3-fold the human value). Fetal development was unaffected in rabbits. Placental transfer of raltegravir to the fetus was substantial in rats, but minimal in rabbits.
 It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats, in which mean drug concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking Isentress. In addition, it is recommended that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

4.7 Effects on Ability to Drive and Use Machines

Certain side effects that have been reported with Isentress or Isentress HD may affect some patients' ability to drive or operate machinery. Individual responses to Isentress or Isentress HD may vary (see Section 4.8).

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience - adults.

Treatment-experienced.

The safety assessment of Isentress in treatment-experienced patients is based on the pooled safety data from the randomised clinical studies, BENCHMRK 1 and BENCHMRK 2 reported using the recommended dose of Isentress 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 1051 patient-years in the group receiving Isentress 400 mg b.i.d. and 322 patient-years in the group receiving placebo.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
For patients in the group receiving Isentress 400 mg twice daily + OBT and the comparator group receiving placebo + OBT in the pooled analysis for studies BENCHMRK 1 and BENCHMRK 2, the most commonly reported clinical adverse experiences (> 10%) of all intensities and regardless of causality were: diarrhoea in 26.6% and 24.9%, nausea in 13.6% and 16.0%, headache in 12.1% and 13.5%, nasopharyngitis in 14.3% and 8.9%, fatigue in 12.1% and 5.9%, upper respiratory tract infection in 15.8% and 10.1%, pyrexia in 9.7% and 13.9%, vomiting in 8.9% and 11.0% of patients respectively.
Drug related adverse experiences - treatment experienced. The clinical adverse experiences listed below were considered by investigators to be of moderate to severe intensity and causally related to Isentress or placebo alone or in combination with OBT:
Common adverse reactions. Drug-related clinical adverse experiences of moderate to severe intensity occurring in ≥ 2% of treatment experienced adult patients in either treatment group are presented in Table 4.
Less common adverse reactions. Drug related clinical adverse experiences occurring in less than 2% of treatment experienced patients (n=462) receiving Isentress + OBT and of moderate to severe intensity are listed below by system organ class:

Cardiac disorders.

Ventricular extrasystoles.

Ear and labyrinth disorders.

Vertigo.

Eye disorders.

Visual impairment.

Gastrointestinal disorders.

Diarrhoea, nausea, abdominal pain, abdominal distension, abdominal pain upper, vomiting, constipation, abdominal discomfort, dyspepsia, flatulence, gastritis, gastro-oesophageal reflux disease, dry mouth, eructation.

General disorders and administration site conditions.

Asthenia, fatigue, pyrexia, chills, face oedema, peripheral oedema.

Hepatobiliary disorders.

Hepatitis.

Immune system disorders.

Drug hypersensitivity.

Infections and infestations.

Herpes simplex, genital herpes, gastroenteritis.

Investigations.

Weight decreased, weight increased.

Metabolism and nutrition disorders.

Diabetes mellitus, dyslipidaemia, increased appetite, decreased appetite.

Musculoskeletal and connective tissue disorders.

Arthralgia, myalgia, back pain, musculoskeletal pain, osteoporosis, polyarthritis.

Nervous system disorders.

Dizziness, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor.

Psychiatric disorders.

Depression, insomnia, anxiety.

Renal and urinary disorders.

Nephritis, nephrolithiasis, nocturia, renal failure, tubulointerstitial nephritis.

Reproductive system and breast disorders.

Gynaecomastia.

Respiratory, thoracic and mediastinal disorders.

Epistaxis.

Skin and subcutaneous tissue disorders.

Lipodystrophy acquired, rash, hyperhidrosis, dermatitis acneiform, erythema, lipohypertrophy, night sweats, rash macular, rash maculopapular, rash pruritic, xeroderma, prurigo, lipoatrophy, pruritus.
Discontinuations. In the pooled analyses for studies P018 and P019, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 4.5% in patients receiving Isentress + OBT and 5.4% in patients receiving placebo + OBT.
Serious events. The following serious drug-related clinical adverse experiences were reported in the clinical studies, gastritis, hepatitis, renal failure, genital herpes, accidental overdose.
In a Phase I study of healthy volunteers, one patient developed a serious rash that required hospitalisation and treatment with oral and topical corticosteroids. This rash occurred several days after darunavir was added to Isentress. The patient discontinued study therapy and the rash eventually resolved.

Clinical trials experience - treatment naive.

The safety of Isentress was evaluated in HIV-1 infected treatment-naive subjects in 2 Phase III studies: STARTMRK (Protocol 021) evaluated Isentress 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate and ONCEMRK (Protocol 292) evaluated Isentress HD 1200 mg (2 x 600 mg) once daily versus Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate.

STARTMRK (protocol 021; Isentress 400 mg twice daily).

The following safety assessment of Isentress in treatment-naive patients is based on the randomised double-blind active controlled study of treatment-naive patients, protocol 021 (STARTMRK) with Isentress 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir disoproxil fumarate 245 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir disoproxil fumarate (N=282). During double-blind treatment, the total follow-up for patients with Isentress 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for patients with efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.
Numbers (%) of patients with clinical adverse experiences and with drug-related adverse experiences in the group receiving Isentress, were less frequent than in the group receiving efavirenz. In this study, the rates of discontinuation of therapy due to adverse experiences (clinical and laboratory) were 5.0% in patients receiving Isentress + emtricitabine (+) tenofovir disoproxil fumarate and 10.0% in patients receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate. (See Table 5.)
CNS events. In treatment naive patients (STARTMRK) central nervous system (CNS) adverse experiences, as measured by proportion of patients with 1 or more CNS symptoms (described below), were reported significantly less frequently in the group receiving Isentress + emtricitabine (+) tenofovir disoproxil fumarate as compared with the group receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate, p < 0.001, < 0.001 and < 0.001 for cumulative events through Weeks 8, 48 and 96, respectively. In the group receiving Isentress, the percentage of patients with 1 or more CNS symptoms was 20.3% compared to 52.1% in the group receiving efavirenz by Week 8, and 26.3% compared to 58.5% by Week 48 and 28.8% compared to 60.6% by Week 96. CNS adverse experiences for this analysis were dizziness, insomnia, concentration impaired, somnolence, depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, auditory hallucination, completed suicide and major depression.
Drug related adverse experiences - treatment naive. The clinical adverse reactions listed below were considered by investigators to be of moderate to severe intensity and causally related to Isentress or efavirenz alone or in combination with emtricitabine (+) tenofovir disoproxil fumarate.
Drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥ 2% of treatment-naive adult patients are presented in Table 6.
Less common adverse reactions. Drug related clinical adverse experiences, occurring in less than 2% of treatment-naive patients (n=281) receiving Isentress + emtricitabine (+) tenofovir disoproxil fumarate and of moderate to severe intensity are listed below by System Organ Class.

Blood and lymphatic system disorders.

Lymph node pain, neutropenia, anaemia, lymphadenopathy.

Ear and labyrinth disorders.

Tinnitus, vertigo.

Gastrointestinal disorders.

Diarrhoea, abdominal pain, vomiting, abdominal pain upper, dyspepsia, erosive duodenitis, gastro-oesophageal reflux disease, abdominal distension.

General disorders and administration site conditions.

Fatigue, asthenia, submandibular mass.

Hepatobiliary disorders.

Hepatitis alcoholic.

Immune system disorders.

Immune reconstitution syndrome.

Infections and infestations.

Herpes zoster, gastroenteritis, folliculitis, lymph node abscess.

Metabolism and nutrition disorders.

Decreased appetite, hypercholesterolaemia, body fat disorder.

Musculoskeletal and connective tissue disorders.

Arthritis, neck pain.

Nervous system disorders.

Dizziness, hypersomnia, somnolence, memory impairment.

Psychiatric disorders.

Abnormal dreams, nightmare, anxiety, mental disorder, confusional state, depression, major depression, suicide attempt.

Renal and urinary disorders.

Nephrolithiasis.

Reproductive system and breast disorders.

Erectile dysfunction.

Skin and subcutaneous tissue disorders.

Acne, alopecia, skin lesion, lipoatrophy.
Serious events. The following serious drug-related adverse experiences were reported in the clinical study, STARTMRK in treatment-naive patients receiving Isentress + emtricitabine (+) tenofovir disoproxil fumarate: anaemia, immune reconstitution syndrome, mental disorder, suicide attempt, depression.

ONCEMRK (protocol 292; Isentress HD 1200 mg [2 x 600 mg] once daily).

The safety of Isentress HD 1200 mg (2 x 600 mg) once daily was assessed in one randomised double-blind active controlled study in 797 treatment-naive HIV-1 infected patients, comparing 531 patients receiving Isentress HD 1200 mg (2 x 600 mg) once daily with 266 patients receiving Isentress 400 mg twice daily, each in combination with emtricitabine (+) tenofovir disoproxil fumarate. The total follow-up for patients on Isentress HD 1200 mg (2 x 600 mg) once daily was 913 patient-years and for Isentress 400 mg twice daily was 450 patient-years.
The proportion of patients with drug-related clinical and laboratory adverse experiences in the group receiving Isentress HD 1200 mg (2 x 600 mg) once daily, and the group receiving Isentress 400 mg twice daily were generally similar (26%, 1.3% versus 26.7%, 2.3%, respectively).
The rates of discontinuation of therapy due to clinical and laboratory adverse experiences were 0.9% and 0.4% in patients receiving Isentress HD 1200 mg (2 x 600 mg) once daily and 2.3% and 0% in patients receiving Isentress 400 mg twice daily.
The most commonly reported clinical adverse experiences (> 10% in either treatment group), of all intensities and regardless of causality, respectively, were headache (16.0% versus 13.9%), nausea (13.6% versus 12.8%), diarrhoea (13.4% versus 12.8%), upper respiratory tract infection (12.6% versus 10.2%) and nasopharyngitis (12.2% versus 9.8%).
There were no drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥ 2% of patients reported in either treatment group.
The rates of serious clinical adverse experiences were similar between patients receiving Isentress HD 1200 mg (2 x 600 mg) once daily and in patients receiving Isentress 400 mg twice daily (9.2% versus 15.8%, respectively). The rates of serious drug related clinical adverse experiences were also similar between the treatment groups (0.2% versus 0.8%, respectively).

Selected adverse experiences - adults - treatment experienced and naive.

Cancers. In studies of Isentress 400 mg twice daily, cancers were observed in treatment experienced patients who initiated Isentress or placebo, both with OBT, and in treatment-naive patients who initiated Isentress or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving Isentress and the group receiving the comparator.
Creatine kinase laboratory abnormalities. Grade 2-4 creatine kinase laboratory abnormalities were observed in individuals treated with Isentress (see Table 7). Myopathy and rhabdomyolysis have been reported; however, the relationship of Isentress to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.
Rash. Rash occurred more commonly in treatment-experienced patients receiving regimens containing Isentress + darunavir compared to patients receiving Isentress without darunavir or darunavir without Isentress. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash. Rash occurred less commonly in treatment-naive patients receiving Isentress compared with efavirenz, each in combination with emtricitabine (+) tenofovir disoproxil fumarate.
Patients with co-existing conditions.

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

In Phase III studies of Isentress patients with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In the treatment experienced studies, BENCHMRK 1 and BENCHMRK 2 (Protocol 018 and Protocol 019), 16% of all patients (114/699) were co-infected; in the treatment-naive studies, STARTMRK (Protocol 021) and ONCEMRK (Protocol 292), 6% (34/563) and 2.9% (23/797), respectively, were co-infected. In general, the safety profile of Isentress in patients with hepatitis B and/or hepatitis C co-infection was similar to that in patients without hepatitis B and/or hepatitis C co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C co-infection for both treatment groups.

Paediatric adverse experiences.

Isentress has been studied in 126 antiretroviral treatment experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 (see Section 5.1). Of the 126 patients, 96 received the recommended dose of Isentress.
In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through week 24 were comparable to those observed in adults. These safety data reflect 24 weeks of treatment.
One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behaviour and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.
One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

Laboratory abnormalities.

Treatment-experienced. The percentages of treatment experienced adult patients receiving either Isentress 400 mg twice daily or placebo (both with OBT), in BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 7.
Treatment-naive.

STARTMRK (protocol 021; Isentress 400 mg twice daily).

The percentages of treatment-naive adult patients receiving either Isentress 400 mg twice daily or efavirenz (both with emtricitabine (+) tenofovir disoproxil fumarate) in P021 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 8.
Lipids, change from baseline - adults. Through 240 weeks of therapy, Isentress demonstrated minimal effects on serum lipids with small increases in total cholesterol, HDL-C, LDL-C, triglycerides and non-HDL-C. The group treated with efavirenz had a significantly higher mean change from baseline in total cholesterol, HDL-C, LDL-C, triglycerides, and non-HDL-C (see Table 9, Lipids, change from baseline).
Changes from baseline in fasting lipids are shown in Table 9.

ONCEMRK (protocol 292; Isentress HD 1200 mg [2 x 600 mg] once daily).

The percentages of patients receiving either Isentress HD 1200 mg (2 x 600 mg) once daily or Isentress 400 mg twice daily in P292 with selected Grade 2 to 4 laboratory abnormalities that represent a worsening Grade from baseline are presented in Table 10.

Postmarketing experience.

The following additional adverse experiences have been reported in postmarketing experience without regard to causality:

Blood and lymphatic system disorders.

Thrombocytopenia.

Hepatobiliary disorders.

Hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis.

Nervous system disorders.

Cerebellar ataxia.

Psychiatric disorders.

Depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviours.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS).

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

No specific information is available on the treatment of overdosage with Isentress or Isentress HD. Multiple doses as high as 1800 mg (3 x 600 mg) q.d. for 28 days and 800 mg b.i.d. were studied in Phase I without evidence of toxicity. Occasional doses of 2400 mg per day were taken in Phase III studies without evidence of toxicity. Based upon available data, raltegravir appears to be well tolerated at doses up to 800 mg b.i.d. and when administered with drugs that increase exposure by 50-70% (such as tenofovir disoproxil fumarate and atazanavir). Raltegravir had a wide therapeutic margin; thus the potential for toxicity as a result of overdose is limited.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which Isentress or Isentress HD may be dialyzable is unknown.
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.

Raltegravir inhibits the catalytic activity of HIV integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome during the early phase of infection. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β and γ.

Microbiology.

Raltegravir at concentrations of 31 ± 20 nanoM resulted in 95% inhibition (IC95) of viral replication (relative to an untreated virus infected culture) in human T-lymphoid cell cultures infected with the cell line adapted HIV-1 variant H9IIIB. In addition, raltegravir at concentrations of 6 to 50 nanoM resulted in 95% inhibition of viral replication in cultures of mitogen activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nanoM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (IC95 = 6 nanoM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with nucleoside analog reverse transcriptase inhibitors (zidovudine, zalcitabine, stavudine, abacavir, tenofovir, didanosine or lamivudine); non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine or delavirdine); protease inhibitors (indinavir, saquinavir, ritonavir, amprenavir, lopinavir, nelfinavir or atazanavir); or the entry inhibitor enfuvirtide.

Drug resistance.

The mutations observed in HIV-1 integrase that contributed to raltegravir resistance (evolved either in vitro or in patients treated with raltegravir) generally included a substitution at either Y143 (changed to C, H or R) or Q148 (changed to H, K or R) or N155 (changed to H) plus one or more additional mutations (e.g. L74I/M, E92Q, E138A/K, G140A/S or V151I).
Recombinant viruses containing a single primary mutation (Q148H, K or R, or N155H) displayed decreased replication capacity and reduced susceptibility to raltegravir in vitro. Secondary mutations further decrease susceptibility to raltegravir and sometimes acted as compensatory mutations for viral replication capacity. In phase 3 studies, integrase genotype data were obtained from about half of the patients experiencing virologic failure by 16 weeks while taking raltegravir. Viruses isolated from the majority of these patients had a signature raltegravir resistance mutation (N155H or Q148H, K or R) along with one or more additional integrase mutations conferring higher-level raltegravir resistance.

Cardiac electrophysiology.

In a randomized, placebo-controlled, crossover study, 31 healthy individuals were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. There was no effect on the QTc interval. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400-mg dose.

Clinical trials.

Adults.

The evidence of durable efficacy of Isentress 400 mg twice daily is based on the analyses of 96 week data from 2 randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (protocols 018 and 019), in antiretroviral treatment experienced HIV-1 infected adult patients and the analysis of 240-week data from a randomized, double-blind, active-control trial, STARTMRK (P021) evaluating Isentress 400 mg twice daily in treatment-naive adult patients, and analysis of 96-week data from a randomized, doubled-blind, active-control trial, ONCEMRK (P292) evaluating Isentress HD 1200 mg (2 x 600 mg) once daily in treatment-naive adult patients.
Treatment-experienced patients. BENCHMRK 1 and BENCHMRK 2 are Phase III studies to evaluate the safety and antiretroviral activity of Isentress 400 mg b.i.d. in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 Classes (NRTIs, NNRTIs, PIs) of antiretroviral therapies. Randomisation was stratified by degree of resistance to PI (1 PI vs. > 1 PI) and the use of enfuvirtide in the OBT. Prior to randomisation, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.
Table 11 shows the demographic characteristics between patients in the group receiving Isentress 400 mg b.i.d. and patients in the group receiving placebo.
Table 12 compares the characteristics of optimised background therapy at baseline in the group receiving Isentress 400 mg b.i.d. and patients in the control group.
Week 48 and 96 outcomes for the 699 patients randomised and treated with the recommended dose of Isentress 400 mg b.i.d. or comparator in the pooled BENCHMRK 1 and 2 studies are shown in Table 13.
The mean decreases in plasma HIV-1 RNA from baseline were 1.81 log10 copies/mL in the Isentress 400 mg b.i.d. arm and 0.75 log10 copies/mL for the control arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving Isentress 400 mg b.i.d. (118 cells/mm3) than in the control arm (47 cells/mm3).
The percent (95% confidence interval) of patients achieving HIV RNA < 50 copies/mL over time is displayed in Figure 1 as Non-completer = Failure Approach (NC=F).
Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 14. Higher response rates were observed in patients with Genotypic Sensitivity Score (GSS) > 0. Patients with GSS or Phenotypic Sensitivity Score (PSS) = 0 had a higher risk of developing resistance to raltegravir. Raltegravir should be used in combination with at least one other active agent to enhance benefit and to reduce the risk of virologic failure and development of resistance to raltegravir.

Switch of suppressed patients from lopinavir (+) ritonavir to raltegravir.

The SWITCHMRK 1 and 2 studies evaluated HIV-infected patients receiving suppressive (screening HIV RNA < 50 copies/mL; stable regimen > 3 months) therapy with lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors and randomised them 1:1 to continue lopinavir (+) ritonavir 2 tablets twice daily (n=174 and n=178, respectively) or replace lopinavir (+) ritonavir with raltegravir 400 mg twice daily (n=174 and n=176, respectively). Patients with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.
These studies were terminated after the primary efficacy analysis at Week 24 because they failed to demonstrate non-inferiority of raltegravir versus lopinavir (+) ritonavir. In both studies at Week 24, suppression of HIV RNA to less than 50 copies/mL was maintained in 84.4% of the raltegravir group versus 90.6% of the lopinavir (+) ritonavir group, (Non-completer = Failure). In patients who had never experienced virological failure before study entry, similar virologic response rates were seen in the raltegravir and the lopinavir (+) ritonavir groups.
Treatment-naive patients.

STARTMRK (protocol 021; Isentress 400 mg twice daily).

STARTMRK (Protocol 21) is a phase III study to evaluate the safety and antiretroviral activity of Isentress 400 mg b.i.d. + emtricitabine (+) tenofovir disoproxil fumarate versus efavirenz + emtricitabine (+) tenofovir disoproxil fumarate in treatment-naive HIV-infected patients aged 18 years or older with HIV RNA > 5000 copies/mL and with no baseline resistance to efavirenz, tenofovir disoproxil fumarate, or emtricitabine. Randomisation was stratified by screening HIV RNA level (≤ 50,000 copies/mL; and > 50,000 copies/mL) and by hepatitis B or C co-infection status.
Table 15 shows the demographic characteristics between patients in the group receiving Isentress 400 mg b.i.d and patients in the group receiving efavirenz.

Results 48-week and 240-week analyses.

With respect to the primary efficacy endpoint (based on a Non-Completer=Failure approach), the proportion (%) of patients achieving HIV RNA < 50 copies/mL at Week 48 was 241/280 (86.1%) in the group receiving Isentress and 230/281 (81.9%) in the group receiving efavirenz. The treatment difference (Isentress-efavirenz) was 4.2% with an associated 95% CI of (-1.9, 10.3) establishing that Isentress is non-inferior to efavirenz (p-value for non-inferiority < 0.001). At Week 240, the treatment difference (Isentress-efavirenz) was 9.5% with an associated 95% CI of (1.7, 17.3).
Week 48 and Week 240 outcomes for patients on the recommended dose of Isentress 400 mg twice daily from STARTMRK are shown in Table 16.

Efficacy by viral subtypes.

A total of 52 non-Clade B subtypes were identified: Clade A (4), A/C (1) A/G (2), A1 (1), AE (29), AG (12), BF (6), C (37), D (2), F (2), F1 (5), G (2), Complex (3). Efficacy in terms of the proportion of patients achieving HIV-RNA < 50 copies/mL at Week 96 was achieved by 52/55 (94.5%) of patients with non-B subtypes and 173/195 (88.7%) of patients with B subtype.
Figure 2 presents the proportion of patients with plasma HIV RNA < 50 copies/mL over time by treatment group. Patients on Isentress achieved viral suppression (HIV RNA < 50 copies/mL) earlier than those receiving EFV, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Through 240 weeks of treatment, 71% in the group receiving Isentress 400 mg b.i.d. and 61% in the comparator group achieved HIV RNA < 50 copies/mL (NC=F approach).
At week 240, the treatment difference (raltegravir-efavirenz) was 9.5% favouring raltegravir with an associated 95% CI of (1.7, 17.3). Therefore, the proportion of patients achieving HIV RNA < 50 copies/mL in raltegravir treatment group was non-inferior to that of efavirenz, as the lower bound of the 95% CI for treatment difference exceeded the pre-defined non-inferiority bound of -12 percentage points.
Patients receiving Isentress achieved viral suppression (HIV RNA < 50 copies/mL) earlier than those receiving efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate.
In the STARTMRK trial of combination antiretroviral therapy in treatment-naive patients, Isentress with emtricitabine (+) tenofovir disoproxil fumarate demonstrated consistent virologic and immunologic efficacy relative to efavirenz with emtricitabine (+) tenofovir disoproxil fumarate across demographic and baseline prognostic factors, including: baseline plasma HIV RNA level > 100,000 copies/mL, baseline CD4 cells ≤ 50 cells/mm3, demographic groups (including age, gender, region, and race), viral hepatitis co-infection status (hepatitis B and/or C) and viral subtypes (comparing non-Clade B as a group to Clade B).
Consistent efficacy of Isentress was observed in all HIV subtypes with 89.6% (155/173) and 87.0% (40/46) of patients with B and non-B subtypes respectively, achieving HIV RNA < 50 copies/mL at week 240 (OF approach).

ONCEMRK (protocol 292; Isentress HD 1200 mg [2 x 600 mg] once daily).

ONCEMRK is a Phase III study to evaluate the safety and antiretroviral activity of Isentress HD 1200 mg (2 x 600 mg) once daily versus Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naive HIV-infected patients with HIV RNA ≥ 1000 copies/mL. Randomisation was stratified by screening HIV RNA level (≤ 100,000 copies/mL; and > 100,000 copies/mL) and by hepatitis status.
Table 17 shows the demographic characteristics for both treatment groups.
The Isentress HD 1200 mg (2 x 600 mg) once daily regimen was non-inferior to the Isentress 400 mg twice daily regimen at both Weeks 48 and 96. At Week 48 88.9% versus 88.3% of once-daily and twice-daily patients, respectively had HIV RNA < 40 copies/mL. A summary of antiretroviral response and immunologic effect at Week 96 is shown in Table 18.
Week 96 outcomes by the Snapshot Approach at Week 96 are shown in Table 19.
Figure 3 presents the proportion of patients with HIV RNA < 40 copies/mL over time by treatment group. Through 96 weeks of treatment 81.5% in the group receiving Isentress HD 1200 mg (2 x 600 mg) once daily and 80.1% in the group receiving Isentress 400 mg twice daily achieved HIV RNA < 40 copies/mL (NC=F approach).
In the ONCEMRK trial, Isentress HD 1200 mg (2 x 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels > 100,000 copies/mL and > 500,000 copies/mL, demographic groups (including age, gender, race, ethnicity and region), viral hepatitis co-infection status (hepatitis B and/or C), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).
In the sub-group efficacy analysis by baseline CD4 cell counts at week 96, Isentress HD demonstrated consistent virologic efficacy relative to Isentress 400 mg twice daily. In patients with baseline CD4 cell counts > 200 cells/mm3, 91.4% and 92.2% in the once daily group and twice daily group, respectively, achieved HIV-1 RNA < 40 copies/mL [treatment difference of -0.8 (95% CI: -5.1, 4.3)]. In patients with baseline CD4 cell counts > 50 and ≤ 200 cells/mm3, 81.1% and 80.0% in the once daily group and twice daily group, respectively, achieved HIV-1 RNA < 40 copies/mL [treatment difference of 1.1 (95% CI: -16.2, 22.4)]. The efficacy in patients with baseline CD4 cell counts of less than 50 cells/mm3 was numerically lower for the once daily regimen (66.7% (6/9) versus 80.0% (4/5) with a treatment difference of -13.3% (95% CI:-53.7, 38.9)); however, the sample size was small (nine patients in the raltegravir once daily group and five in the twice daily group) and the findings were not statistically significant, hence it is difficult to draw meaningful conclusions.
Consistent efficacy in patients receiving Isentress HD 1200 mg (2 x 600 mg) once daily was observed across HIV subtypes with 90.0% (270/300) and 89.5% (162/181) of patients with B and non-B subtypes, respectively, achieving HIV RNA < 40 copies/mL at week 96 (OF approach).

Paediatric patients.

IMPAACT P1066 is a Phase I/II open label multicentre trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 antiretroviral treatment experienced children and adolescents 2 through to 18 years of age. Patients were stratified by age, enrolling adolescents first and then successively younger children. Patients received either the 400 mg tablet formulation (6 through 18 years of age) or the chewable tablet formulation (2 through 11 years of age). Raltegravir was administered with an optimised background regimen.
The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional patients were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 patients, 96 received the recommended dose of Isentress (see Section 4.2).
These 96 patients had a median age of 13 (range 2 to 18) years, were 51% female, 34% Caucasian and 59% black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0-2361) and median CD4% was 23.3% (range: 0-44). Overall, 8% had baseline plasma HIV-1 RNA > 100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most patients had previously used at least one NNRTI (78%) or one PI (83%).
Ninety-three (97%) patients 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At week 24, using observed failure (OF) approach to handle missing data, 72% (68/95) achieved ≥ 1 log10 HIV RNA drop from baseline or ≤ 400 copies/mL (a composite outcome) with 95% CI of (61.4%, 80.4%); 54% (51/95) achieved HIV RNA < 50 copies/mL with 95% CI of (43.2%, 64%). The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).
Seventy-two (95%) patients 6 to 18 years of age completed 48 weeks of treatment (4 discontinued due to non-compliance). At week 48, using OF approach to handle missing data, 77% (55/71) achieved ≥ 1 log10 HIV RNA drop from baseline or < 400 copies/mL with 95% CI of (66.0%, 86.5%); 56% (40/71) achieved HIV RNA < 50 copies/mL with 95% CI of (44.0%, 68.1%). The mean CD4 count (percent) increase from baseline to Week 48 was 155 cells/mm3 (4.7%).

5.2 Pharmacokinetic Properties

Absorption - adults.

As demonstrated in healthy volunteers administered single oral doses of raltegravir (400 mg film coated tablet) in the fasted state, raltegravir 400 mg twice daily is rapidly absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12 hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. In patients on 400 mg twice daily monotherapy, raltegravir drug exposures were characterised by a geometric mean AUC0-12 hr of 14.3 microM.hr and C12 hr of 142 nanoM. With twice-daily dosing, pharmacokinetic steady state is achieved rapidly, within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax and evidence of slight accumulation in C12 hr. The absolute bioavailability of raltegravir has not been established.
Raltegravir 1200 mg (2 x 600 mg) once daily is also rapidly absorbed with median Tmax ~1.5 to 2 hours in the fasted state, and generates a sharper absorption peak with a tendency to higher Cmax in comparison to raltegravir twice daily (1 x 400 mg tablet twice daily). In addition, relative to the raltegravir 400 mg formulation the raltegravir 600 mg formulation used in the 1200 mg (2 x 600 mg) once daily dosing regimen has higher relative bioavailability (by 21 to 66%), Once absorbed, both formulations of raltegravir exhibit similar systemic pharmacokinetics. In patients, after 1200 mg once daily raltegravir dosing, steady state AUC0-24 was 53.7 h.microM, C24 was 75.6 nanoM, and median Tmax was 1.50 h. Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration.

Effect of food on oral absorption.

Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of 400 mg twice daily raltegravir following a moderate-fat meal did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12 hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of 400 mg twice daily raltegravir following a high fat meal increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of 400 mg twice daily raltegravir following a low fat meal decreased AUC and Cmax by 46% and 52%, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.
A single dose food effect study demonstrated that 1200 mg (2 x 600 mg) once daily had similar or smaller food effects when studied under high-fat and low-fat meal conditions when compared to 400 mg twice daily. Administration of a low fat meal with Isentress HD 1200 mg (2 x 600 mg) once daily resulted in a 42% decrease in AUC0-last, 52% decrease in Cmax, and 16% decrease in C24hr. Administration of a high fat meal resulted in a 1.9% increase in AUC0-last, 28% decrease in Cmax, and 12% decrease in C24hr.

Distribution - adults.

Raltegravir is approximately 83% bound to human plasma proteins in vitro over the concentration range of 2 to 10 microM.
In three studies in HIV-infected pregnant women who received raltegravir 400 mg twice daily, raltegravir was found to readily cross the placenta, with median cord blood/maternal blood raltegravir concentration ratios reported as 1.5, 1.21 and 1.48. (See Section 5.2, Pregnancy).
In two studies of HIV-1 infected patients who received raltegravir 400 mg twice daily, raltegravir was readily detected in the cerebrospinal fluid. In the first study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. In the second study (n=16), the median cerebrospinal fluid concentration was 3% (range 1 to 61%) of the corresponding plasma concentration. These median proportions are approximately 3- to 6-fold lower than the free fraction of raltegravir in plasma.
Raltegravir readily crossed the placenta in rats. Raltegravir did not penetrate the brain of rats to any appreciable extent.

Metabolism and excretion - adults.

The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabelled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in laboratory animal species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.
Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Characteristics in patients.

Gender.

A study of the pharmacokinetics of raltegravir 400 mg twice daily was performed in young healthy males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy individuals and 28 HIV patients receiving raltegravir monotherapy with fasted administration. The effect of gender was also evaluated in a population pharmacokinetic (PK) analysis of concentration data from 80 healthy individuals and HIV patients receiving raltegravir alone or in combination with other drugs and in fasted and fed conditions. There were no clinically important pharmacokinetic differences due to gender. For raltegravir 1200 mg (2 x 600 mg) once daily, based on population pharmacokinetic analysis, there were no clinically important pharmacokinetic differences due to gender. No dosage adjustment is necessary.

Age.

The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis and the population PK analysis. There was no clinically meaningful effect of age on raltegravir pharmacokinetics. No dosage adjustment is necessary.

Paediatric.

Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has higher oral bioavailability compared to the 400 mg tablet. In this study, administration of the chewable tablet with a high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax, and 188% increase in C12 hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food. The doses recommended for HIV-infected children and adolescents 2 to 18 years of age (see Section 4.2) resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. Table 20 displays pharmacokinetic parameters in the 400 mg tablet (6 to 18 years of age) and the chewable tablet (2 to 11 years of age).
The pharmacokinetics of raltegravir in children less than 2 years of age has not been established.
Isentress HD 1200 mg (2 x 600 mg) once daily was not evaluated in a paediatric clinical study, however, population PK modeling and simulation analyses were conducted. Given that all the paediatric simulated exposures are within the adult exposures observed from Phase III ONCEMRK (Protocol 292), and that there are no safety concerns at the same exposure values, a weight cutoff of 40 kg is deemed adequate to achieve a safe administration of Isentress HD 1200 mg (2 x 600 mg) once daily while maintaining clinical efficacy. These results support the use of Isentress HD 1200 mg (2 x 600 mg) once daily in paediatric patients weighing at least 40 kg.

Race.

The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis for Isentress 400 mg twice daily, and no clinically meaningful effect of race on raltegravir pharmacokinetics was concluded. For Isentress HD 1200 mg (2 x 600 mg) once daily, population PK analysis also demonstrated that the impacts of race and ethnicity are not clinically meaningful. No dosage adjustment is necessary.

Body mass index (BMI) and body weight.

The composite analysis assessed the effect of BMI on the pharmacokinetics of raltegravir. There was no clinically meaningful effect of BMI on raltegravir pharmacokinetics. Additionally, no clinically meaningful effect of bodyweight on raltegravir pharmacokinetics was identified in the population PK analysis for both Isentress 400 mg twice daily and Isentress HD 1200 mg (2 x 600 mg) once daily. No dosage adjustment is necessary.

Hepatic insufficiency.

Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in patients with moderate hepatic insufficiency. Additionally, hepatic insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with moderate hepatic insufficiency and healthy individuals. No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. No hepatic impairment study has been conducted with Isentress HD 1200 mg (2 x 600 mg) once daily; however, based on results with Isentress 400 mg twice daily tablet, no clinically meaningful effect is expected for mild and moderate hepatic impairment. The effect of severe hepatic insufficiency on the pharmacokinetics of raltegravir has not been studied.

Renal insufficiency.

Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in patients with severe renal insufficiency. Additionally, renal insufficiency was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy individuals. No dosage adjustment is necessary. No renal impairment study was conducted with Isentress HD 1200 mg (2 x 600 mg) once daily; however, based on results with Isentress 400 mg twice daily tablet, no clinically meaningful effect is anticipated. Because the extent to which Isentress may be dialyzable is unknown, dosing before a dialysis session should be avoided.

UGT1A1 polymorphism.

There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult individuals with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult individuals with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).

Pregnancy.

The pharmacokinetics of raltegravir during pregnancy has been investigated in two clinical studies in which HIV-infected pregnant women received raltegravir-based antiretroviral therapy, at the dose of raltegravir 400 mg twice daily. One study of 42 HIV-infected pregnant women with PK sampling performed at 0-26 weeks and 30-36 weeks of gestation and 6-12 weeks postpartum found that raltegravir exposure during the second and third trimester was approximately half that post-partum. The second study of 22 HIV-infected pregnant women in which PK sampling was performed in the third trimester and more than 2 weeks post-partum found that 11 of 17 patients with complete paired pharmacokinetic curves showed a decrease in raltegravir exposure in the third trimester compared with postpartum; exposure in the third trimester was increased in the other 6 women. As most women had undetectable HIV RNA levels at delivery and mother-to-child-transmission of HIV was not observed among the limited number of maternal-infant pairs, dose modification is not routinely recommended. Decisions based on individual patient monitoring under specialist care are recommended as required.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo tests for clastogenic activity.

Carcinogenicity.

Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was approximately 2-fold greater than (females) or equal to (males) the clinical AUC (54 microM.hr) at the 400-mg twice daily dose. In rats, treatment-related squamous cell carcinomas of the nose/nasopharynx were identified in high- and mid-dose group animals treated with raltegravir for two years. No tumors of the nose/nasopharynx were observed in rats dosed with 50 mg/kg/day in females and 150 mg/kg/day in males at which systemic exposure was approximately 1.5-fold greater than the AUC (54 microM.hr) at the clinical 400-mg twice daily dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Isentress HD 600 mg tablet.

Each tablet contains the following inactive ingredients: microcrystalline cellulose, hypromellose 2910, croscarmellose sodium, magnesium stearate.
In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose 2910, titanium dioxide, triacetin, iron oxide yellow, and iron oxide black. The tablet may also contain trace amounts of carnauba wax.

Isentress 400 mg tablet.

Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate.
In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

Isentress 100 mg chewable tablet.

Each tablet contains the following inactive ingredients: hydroxypropylcellulose, sucralose, saccharin sodium, sodium citrate, mannitol, red iron oxide, yellow iron oxide, ammonium glycyrrhizinate, sorbitol, fructose, natural and artificial flavours (orange, banana and masking that contains aspartame), crospovidone, magnesium stearate, sodium stearyl fumarate, ethylcellulose 20 cP, ammonium hydroxide, medium chain triglycerides, oleic acid, hydroxypropylmethyl cellulose 2910/6cP, macrogol 400.

Isentress 25 mg chewable tablet.

Each tablet contains the following inactive ingredients: hydroxypropylcellulose, sucralose, saccharin sodium, sodium citrate, mannitol, yellow iron oxide, ammonium glycyrrhizinate, sorbitol, fructose, natural and artificial flavours (orange, banana and masking that contains aspartame), crospovidone, magnesium stearate, sodium stearyl fumarate, ethylcellulose 20 cP, ammonium hydroxide, medium chain triglycerides, oleic acid, hydroxypropylmethyl cellulose 2910/6cP, macrogol 400.

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

Isentress and Isentress HD film-coated and Isentress chewable tablets should be stored below 30°C.

6.5 Nature and Contents of Container

Film-coated tablets.

Isentress HD: 600 mg yellow, oval tablet debossed with the corporate logo and "242" on one side and plain on the other.
Isentress: 400 mg pink, oval, biconvex tablet debossed with "227" on one side and plain on the other.
Available in HDPE bottles of 60.

Chewable tablets.

Isentress: 100 mg pale orange, oval-shaped, orange-banana flavoured, scored chewable tablets with the corporate logo and "477" on opposite sides of the score and scored on the reverse side.
25 mg pale yellow, round, orange-banana flavoured, chewable tablets with the corporate logo on one side and "473" on the other side.
Available in HDPE bottles of 60.

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

Isentress (raltegravir) is an HIV integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1).

Chemical structure.

The chemical name for raltegravir potassium is N-[(4-Fluorophenyl)methyl]- 1,6-dihydro-5-hydroxy-1-methyl- 2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino]ethyl]- 6-oxo-4-pyrimidinecarboxamide monopotassium salt.
The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:

CAS number.

871038-72-1.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (schedule 4).

Summary Table of Changes