Norvir 100mg oral powder sachets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Ritonavir
Available from:
AbbVie Ltd
ATC code:
J05AE03
INN (International Name):
Ritonavir
Dosage:
100mg
Pharmaceutical form:
Powder
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 8054083008646

Read the complete document

Package leaflet: Information for the user

Norvir 100 mg powder for oral suspension

ritonavir

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you or your child.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Norvir is and what it is used for

What you need to know before you or your child takes Norvir

How to take Norvir

Possible side effects

How to store Norvir

Contents of the pack and other information

1.

What Norvir is and what it is used for

Norvir contains the active substance ritonavir. Norvir is a protease inhibitor used to control HIV

infection. Norvir is used in combination with other anti-HIV medicines (antiretrovirals) to control

your HIV infection. Your doctor will discuss with you the best combination of medicines for you

Norvir is used by children 2 years of age or older, adolescents and adults who are infected with HIV,

the virus which causes AIDS.

2.

What you need to know before you or your child takes Norvir

Do not take Norvir

if you are allergic to ritonavir or any of the other ingredients of Norvir (see section 6).

if you have severe liver disease.

if you are currently taking any of the following medicines:

astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines

may be available without prescription);

amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine (used to

correct irregular heartbeats);

dihydroergotamine, ergotamine (used to treat migraine headache);

ergonovine, methylergonovine (used to stop excessive bleeding that may occur following

childbirth or an abortion);

clorazepate, diazepam, estazolam, flurazepam, triazolam or oral (taken by mouth)

midazolam (used to help you sleep and/or relieve anxiety);

clozapine, pimozide, (used to treat abnormal thoughts or feelings);

quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder);

lurasidone (used to treat depression);

ranolazine (used to treat chronic chest pain [angina]);

pethidine, piroxicam, propoxyphene (used to relieve pain);

cisapride (used to relieve certain stomach problems);

rifabutin (used to prevent/treat certain infections)*;

voriconazole (used to treat fungal infections)*;

simvastatin, lovastatin (used to lower blood cholesterol);

alfuzosin (used to treat enlarged prostate gland);

fusidic acid (used to treat bacterial infections);

sildenafil if you suffer from a lung disease called pulmonary arterial hypertension that

makes breathing difficult. Patients without this disease may use sildenafil for impotence

(erectile dysfunction) under their doctor’s supervision (see the section on Other

medicines and Norvir);

avanafil or vardenafil (used to treat erectile dysfunction);

colchicine (used to treat gout) if you have kidney and/or liver problems (see the section

on Other medicines and Norvir);

products containing St John’s wort (Hypericum perforatum) as this may stop Norvir from

working properly. St John’s wort is often used in herbal medicines that you can buy

yourself.

* Your doctor may decide that you can take rifabutin and/or voriconazole with a booster (lower

dose) of Norvir but a full dose of Norvir must not be taken together with these two medicines.

If you are currently taking any of these medicines, ask your doctor about switching to a different

medicine while you are taking Norvir.

Also read the list of medicines under ‘Other medicines and Norvir’ for use with certain other

medicines which require special care.

Warnings and precautions

Talk to your doctor before taking Norvir.

Important information

If Norvir is taken in combination with other antiretroviral medicines, it is important that you

also carefully read the leaflets that are provided with these other medicines. There may be

additional information in those leaflets about situations when Norvir should be avoided. If you

have any further questions about Norvir (ritonavir) or the other medicines prescribed, please ask

your doctor or pharmacist.

Norvir is not a cure for HIV infection or AIDS.

People taking Norvir may still develop infections or other illnesses associated with HIV

infection or AIDS. It is therefore important that you remain under the supervision of your

doctor while taking Norvir.

You can still pass on HIV when taking this medicine, although the risk is lowered by effective

antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting

other people.

Tell your doctor if you have/had:

A history of liver disease.

Hepatitis B or C and are being treated with a combination of antiretroviral agents, as you are at

a greater risk of a severe and potentially life threatening reaction because of the effect on the

liver. Regular blood tests may be required to check your liver is working properly.

Haemophilia, as there have been reports of increased bleeding in patients with haemophilia

who are taking this type of medicine (protease inhibitors). The reason for this is not known.

You may need additional medicine to help your blood clot (factor VIII), in order to control any

bleeding.

Erectile dysfunction, as the medicines used to treat erectile dysfunction can cause hypotension

and prolonged erection.

Diabetes, as there have been reports of worsening of or the development of diabetes (diabetes

mellitus) in some patients taking protease inhibitors.

Kidney (renal) disease, since your doctor may need to check the dose of your other medicines

(such as protease inhibitors).

Tell your doctor if you experience:

Diarrhoea or vomiting that is not improving (persistent), as this may reduce how well the

medicines you are taking work.

Feeling sick (nausea), vomiting or have stomach pain, because these may be signs of

inflammation of the pancreas (pancreatitis). Some patients taking Norvir can develop serious

problems with their pancreas. Tell your doctor as soon as possible if this applies to you.

Symptoms of infection – inform your doctor immediately. Some patients with advanced HIV

infection (AIDS) who then start anti-HIV treatment may develop the symptoms of infections

they have had in the past even if they didn’t know they had had them. It is believed that this

happens because the body's immune response improves and helps the body to fight these

infections.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when

the immune system attacks healthy body tissue) may also occur after you start taking medicines

for the treatment of your HIV infection. Autoimmune disorders may occur many months after

the start of treatment. If you notice any symptoms of infection or other symptoms such as

muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk

of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to

seek necessary treatment.

Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty

moving, tell your doctor, as this may be a sign of a problem that can destroy bone

(osteonecrosis). Some patients taking a number of antiretroviral medicines may develop this

disease.

Muscle pain, tenderness or weakness, particularly in combination with antiretroviral therapy

including protease inhibitors and nucleoside analogues. On rare occasions these muscle

disorders have been serious. (See section 4. Possible side effects)

Dizziness, lightheadedness, fainting spells or abnormal heartbeat. Some patients taking

Norvir may experience changes in the electrocardiogram (ECG). Tell your doctor if you have a

heart defect or conduction defect.

If you have any other health concerns, discuss these with your doctor as soon as you can.

Children and adolescents

Norvir is not recommended in children below 2 years of age.

Other medicines and Norvir

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription. There are some medicines you

cannot take at all with Norvir. These are listed earlier in section 2, under ‘Do not take Norvir’.

There are some other medicines that can only be used under certain circumstances as described below.

The following warnings apply when Norvir is taken as a full dose. However, these warnings may also

apply when Norvir is used in lower doses (a booster) with other medicines.

Tell your doctor if you are taking any of the medicines listed below, as special care should be

taken.

Sildenafil or tadalafil for impotence (erectile dysfunction).

The dose and/or frequency of use of these medicines may need to be reduced to avoid

hypotension and prolonged erection. You must not take Norvir with sildenafil if you suffer

from pulmonary arterial hypertension (see also section 2. What you need to know before you

or your child takes Norvir). Tell your doctor if you are taking tadalafil for pulmonary arterial

hypertension.

Colchicine (for gout) as Norvir may raise the blood levels of this medicine. You must not take

Norvir with colchicine if you have kidney and/or liver problems (see also ‘Do not take Norvir

above).

Digoxin (heart medicine). Your doctor may need to adjust the dose of digoxin and monitor you

while you are taking digoxin and Norvir in order to avoid heart problems.

Hormonal contraceptives containing ethinyl oestradiol as Norvir may reduce the effectiveness

of these medicines. It is recommended that a condom or other non-hormonal method of

contraception is used instead. You may also notice irregular uterine bleeding if you are taking

this type of hormonal contraceptive with Norvir.

Atorvastatin or rosuvastatin (for high cholesterol) as Norvir may raise the blood levels of

these medicines. Talk to your doctor before you take any cholesterol-reducing medicines with

Norvir (see also ‘Do not take Norvir’ above).

Steroids (e.g. dexamethasone, fluticasone propionate, prednisolone, triamcinolone) as Norvir

may raise the blood levels of these medicines which may lead to Cushing’s syndrome

(development of a rounded face) and reduce production of the hormone cortisol. Your doctor

may wish to reduce the steroid dose or monitor your side effects more closely.

Trazodone (a medicine for depression) as, unwanted effects like nausea, dizziness, low blood

pressure and fainting can occur when taken with Norvir.

Rifampicin and saquinavir (used for tuberculosis and HIV, respectively) as serious liver

damage can occur when taken with Norvir.

Bosentan, riociguat (used for pulmonary arterial hypertension) as Norvir may increase the

blood levels of this medicine.

There are medicines that may not mix with Norvir because their effects could increase or decrease

when taken together. In some cases your doctor may need to perform certain tests, change the dose or

monitor you regularly. This is why you should tell your doctor if you are taking any medicines,

including those you have bought yourself or herbal products, but it is especially important to mention

these:

amphetamine or amphetamine derivatives;

antibiotics (e.g. erythromycin, clarithromycin);

anticancer treatments (e.g. afatinib, ceritinib, dasatinib, nilotinib, venetoclax, vincristine,

vinblastine);

anticoagulants (e.g. rivaroxaban, vorapaxar, warfarin)

antidepressants (e.g. amitriptyline, desipramine, fluoxetine, imipramine, nefazodone,

nortriptyline, paroxetine, sertraline, trazodone);

antifungals (e.g. ketoconazole, itraconazole);

antihistamines (e.g. loratadine, fexofenadine);

antiretroviral medicines, including HIV-protease inhibitors (amprenavir, atazanavir, darunavir,

fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir), non-nucleoside reverse

transcriptase inhibitors (NNRTI) (delavirdine, efavirenz, nevirapine), and others (didanosine,

maraviroc, raltegravir, zidovudine);

anti-tuberculosis medicine (bedaquiline and delamanid);

antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (simeprevir);

anxiety medicine, buspirone;

asthma medicine, theophylline, salmeterol;

atovaquone, a medicine used to treat a certain type of pneumonia and malaria;

buprenorphine, a medicine used for the treatment of chronic pain;

bupropion, a medicine used to help you stop smoking;

epilepsy medicines (e.g. carbamazepine, divalproex, lamotrigine, phenytoin);

heart medicines (e.g. disopyramide, mexiletine and calcium channel antagonists such as

amlodipine, diltiazem and nifedipine);

immune system medicines (e.g. cyclosporine, tacrolimus, everolimus);

morphine and morphine-like medicines used to treat severe pain (e.g. methadone, fentanyl);

sleeping pills (e.g. alprazolam, zolpidem) and also midazolam administered by injection;

tranquillisers (e.g. haloperidol, risperidone, thioridazine);

colchicine, a treatment for gout.

There are some medicines you cannot take at all with Norvir. These are listed earlier in section 2,

under ‘Do not take Norvir’.

Taking Norvir with food and drink

See section 3.

Pregnancy and breast-feeding

If you think you are pregnant or you are planning to become pregnant, it is very important that

you discuss this with your doctor.

There is a large amount of information on the use of ritonavir (the active ingredient in Norvir) during

pregnancy. In general, pregnant mothers received ritonavir after the first three months of pregnancy

at a lower dose (booster) along with other protease inhibitors. Norvir did not appear to increase the

chance of developing birth defects compared to the general population.

Norvir can pass into breast milk. To avoid transmitting the infection, mothers with HIV must not

breast feed their babies.

Driving and using machines

Norvir can cause dizziness. If you are affected do not drive or use machinery.

3.

How to take Norvir

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure. Take this medicine one or two times a day every day with food.

For doses of exactly 100 mg amounts (100, 200, 300, 400, 500, or 600 mg) pour the entire content of

each sachet over soft food (apple sauce or vanilla pudding) or mix with a small amount of liquid

(water, chocolate milk, or infant formula) and consume entire serving.

For doses less than 100 mg amounts or doses between 100 mg amounts, the content of the entire

sachet is to be mixed with a liquid and then dosed by the appropriate ml volume as told to you

by your doctor using the oral dosing syringe.

For administration using a feeding tube follow the instructions in section ‘How do I take the correct

dose of Norvir powder for oral suspension mixed with liquid?’ Use water to mix the medicine and

follow the feeding tube instructions to administer the medicine.

Recommended doses of Norvir are:

if Norvir is used to boost the effects of other anti-HIV medicines, the typical dose for adults is 1

or 2 sachets once or twice daily. For more detailed dose recommendations, including those for

children, see the Package Leaflet of the anti-HIV medicines Norvir is given in combination

with.

if your doctor prescribes a full dose, adults may be started on a dose of 3 sachets in the morning

and 3 sachets 12 hours later, gradually increasing over a period of up to 14 days to the full dose

of 6 sachets twice daily. Children (2 – 12 years of age) will start with a dose smaller than this

and continue up to the maximum allowed for their size.

Your doctor will advise you on the dosage to be taken.

Norvir should be taken every day to help control your HIV, no matter how much better you feel. If a

side effect is preventing you from taking Norvir, tell your doctor straight away. During episodes of

diarrhoea your doctor may decide that extra monitoring is needed.

Always keep enough Norvir on hand so you don't run out. When you travel or need to stay in the

hospital, make sure you have enough Norvir to last until you can get a new supply.

Norvir powder for oral suspension has a lingering aftertaste. Eating peanut butter, hazelnut chocolate

spread, or black currant syrup immediately after taking the medication may help clear the aftertaste

from your mouth.

Prepare only one dose at a time using the correct number of sachets. When mixing the powder with

food or liquid, be sure to take the whole dose within 2 hours. Do not mix Norvir with anything else

without talking to your doctor or pharmacist.

How do I take the correct dose of Norvir powder for oral suspension mixed with food (full

sachet)?

Follow the instructions below:

Step 1. Before mixing dose of Norvir, collect the

following supplies: (see Figure 1).

Step 2. Check prescription for number of sachets

or call your doctor or pharmacist.

Figure 1

Step 3. Put a small serving of soft food (applesauce or

vanilla pudding) in a cup (see Figure 2).

Figure 2

Step 4. Tear open sachet (see Figure 3).

Figure 3

Step 5. Pour ALL powder from sachet onto food (see

Figure 4).

Figure 4

Step 6. Mix thoroughly (see Figure 5).

Figure 5

Step 7. Feed serving to patient.

Step 8. ENTIRE serving must be eaten (see Figure 6). If

powder residue is left, add more spoonfuls of food and

serve to patient. Use within 2 hours.

Figure 6

Step 9. Place empty sachet in rubbish. Wash and dry

preparation area. Immediately wash the spoon and cup in

warm water and dish soap (see Figure 7). Rinse and

allow to air dry.

Figure 7

How do I take the correct dose of Norvir powder for oral suspension mixed with liquid?

Follow the instructions below:

Figure 1

What you need

Before mixing a dose of Norvir, collect the items

shown in Figure 1.

You may need more than 1 sachet for each dose.

Check the prescription label on the carton or call

your doctor or pharmacist if you are not sure. If

you do need more than 1 sachet, repeat all the

steps with each sachet.

Using the syringe

Reading the scale

a. Each millilitre (ml) is shown as a number

with a big line.

b. Each 0.2 ml is shown as a smaller line

between the numbers.

Check the syringe before each use

You will need to use a new syringe if:

you cannot clean the syringe

you cannot read the scale

you cannot move the plunger

the syringe is damaged or leaking.

Figure 2

Step 1. Fill the syringe

a. Push the plunger all the way into syringe.

b. Place the syringe tip into the liquid.

c. Slowly pull the plunger back to the 10 ml mark

on the syringe (see Figure 2).

Figure 3

Step 2. Move any bubbles to the tip of the

syringe

a. Hold the syringe with the tip pointing up.

b. Tap the syringe with your

other hand. This will move any bubbles to the tip.

c. Pull the plunger down.

Be careful not to pull the plunger out.

d. Tap the syringe again. This will help to break

up the bubbles and make sure they are all at the

tip (see Figure 3).

Figure 4

Step 3. Measure the liquid

a. Keep the syringe pointed up.

b. Slowly push the plunger up until the top of the

plunger is at 9.4 ml - this will remove any bubbles

from the syringe (see Figure 4).

Figure 5

Step 4. Empty the syringe

a. Slowly push the plunger to empty the liquid

from the syringe into the mixing cup (see Figure

Figure 6

Step 5. Pour the powder into the cup

a. Tear open the sachet.

b. Pour all of the powder into the mixing cup.

c. Check if the sachet is empty.

Be careful not to spill any powder outside of

the mixing cup (see Figure 6).

Figure 7

Step 6. Mix the powder and liquid

a.Tightly screw on the lid and keep shaking the

mixing cup hard for at least 90 seconds until all

the lumps have gone.

b. Check for any lumps of powder. If there are

still lumps, keep shaking until they have all gone.

c. The liquid may look cloudy - this is okay.

d. Let the liquid stand for 10 minutes and most of

the bubbles will disappear.

e. You may see some small bubbles on top of the

liquid - this is also okay (see Figure 7).

Figure 8

Step 7. Fill the syringe

a. Push the plunger completely into the syringe.

b. Place the syringe tip at the bottom of the

mixing cup.

c. Slowly pull the plunger back to the 10 ml mark

- try not to pull any bubbles into the syringe (see

Figure 8).

Figure 9

Step 8. Remove any bubbles

a. Hold the syringe with the tip pointing up.

b. Tap the syringe with your other hand. This will

move any bubbles to the tip.

c. Pull the plunger down. Be careful not to pull

the plunger out.

d. Tap the syringe again to break up the bubbles

so they are all at the tip (see Figure 9).

e. Slowly push the plunger until you see a small

amount of liquid at the tip of the syringe.

f. If there are any large air bubbles, empty the

liquid from the syringe into the mixing cup and

start again from Step 7.

Figure 10

Step 9. Measure the dose

a. Check the prescription label on the carton for

the dose in ml. If you are not sure, call your

doctor or pharmacist.

b. Point the syringe into the mixing cup and

slowly push the plunger to the correct ml for the

dose (see Figure 10).

c. If you push out too much liquid, start again

from Step 7. Be careful not to spill the liquid

outside of the mixing cup.

Figure 11

Step 10. Give the medicine to the patient

a. Place the syringe tip against the inside of the

patient’s cheek.

b. Slowly push the plunger to give all of the dose

(see Figure 11).

c. Give the patient the full dose within 2 hours of

opening the sachet.

Step 11. (If required)

If you need to use more than one sachet, repeat the

process from the beginning.

Step 12. After you have finished

a. Place the empty sachet and any left over

medicine from the mixing cup into a rubbish bag.

b. Remove the plunger from the syringe.

c. Hand wash the syringe, plunger, and mixing

cup and lid in warm water and dish soap. Rinse

with water and allow to air dry. Do not wash these

in the dishwasher.

d. Wash and dry the area used to mix the

medicine.

If you take more Norvir than you should

Numbness, tingling, or a “pins and needles” sensation may occur if you take too much Norvir. If you

realise you have taken more Norvir than you were supposed to, contact your doctor or the Accident

and Emergency Department of your nearest hospital straight away.

If you forget to take Norvir

If you miss a dose, take the missed dose as soon as possible. If it is nearly time for the next dose, just

take that one. Do not take a double dose to make up for a forgotten dose.

If you stop taking Norvir

Even if you feel better, do not stop taking Norvir without talking to your doctor. Taking Norvir as

recommended should give you the best chance of delaying resistance to the medicines.

4.

Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.

This is partly linked to restored health and life style, and in the case of blood lipids sometimes to the

HIV medicines themselves. Your doctor will test for these changes.

Like all medicines, Norvir can cause side effects, although not everybody gets them. Also, the side

effects of Norvir when used with other antiretroviral medicines are dependent on the other medicines.

So it is important that you carefully read the side effects section of the leaflets that are provided with

these other medicines.

Very common: may affect more than 1 in 10 people

upper or lower stomach ache

vomiting

diarrhoea (may be severe)

feeling sick (nausea)

flushing, feeling hot

headache

dizziness

pain in the throat

cough

upset stomach or indigestion

a tingling sensation or numbness in

the hands, feet or around the lips and

mouth

feeling weak/tired

bad taste in the mouth

damage to the nerves that can cause

weakness and pain

itching

rash

joint pain and back pain

Common: may affect up to 1 in 10 people

allergic reactions including skin

rashes (may be red, raised, itchy),

severe swelling of the skin and

other tissues

inability to sleep (insomnia)

anxiety

increase in cholesterol

increase in triglycerides

gout

stomach bleeding

inflammation of the liver and yellowing of

skin or whites of the eyes

increase in urination

reduced kidney function

seizures (fits)

low levels of blood platelets

thirst (dehydration)

abnormally heavy periods

wind (flatulence)

loss of appetite

mouth ulcer

muscle aches (pain), tenderness or

weakness

fever

weight loss

laboratory test results:

changes in blood test results

(such as blood chemistry and

blood count)

confusion

difficulty paying attention

fainting

blurred vision

swelling of the hands and feet

high blood pressure

low blood pressure and feeling faint when

getting up

coldness in the hands and feet

acne

Uncommon: may affect up to 1 in 100 people

heart attack

diabetes

kidney failure

Rare: may affect up to 1 in 1,000 people

severe or life threatening skin

reaction including blisters

(Stevens Johnson syndrome, toxic

epidermal necrolysis)

serious allergic reaction (anaphylaxis)

high levels of sugar in the blood

Tell your doctor if you feel sick (nauseous), are vomiting, or have stomach pain, because these may

be signs of an inflamed pancreas. Also tell your doctor if you experience joint stiffness, aches and

pains (especially of the hip, knee and shoulder) and difficulty moving, as this may be a sign of

osteonecrosis. See also section 2. What you need to know before you or your child takes Norvir.

In patients with haemophilia types A and B, there have been reports of increased bleeding while

taking this treatment or another protease inhibitor. Should this happen to you, seek immediate advice

from your doctor.

Abnormal liver function tests, hepatitis (inflammation of the liver), and rarely jaundice, have been

reported in patients taking Norvir. Some people had other illnesses or were taking other medicines.

People with liver disease or hepatitis may have worsening of liver disease.

There have been reports of muscle pain, tenderness or weakness, particularly when taking medicines

to lower cholesterol in combination with antiretroviral therapy, including protease inhibitors and

nucleoside analogues. On rare occasions these muscle disorders have been serious (rhabdomyolysis).

In the event of unexplained or continual muscle pain, tenderness, weakness or cramps, stop taking the

medicine, contact your doctor as soon as possible or go to the Accident and Emergency Department of

your nearest hospital.

Inform your doctor as soon as possible if you experience any symptoms that suggest an allergic

reaction after taking Norvir such as rash, hives or breathing difficulties.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

contact your doctor, pharmacist, Accident and Emergency department or if it is urgent get

immediate medical help.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly (see details below). By reporting

side effects, you can help provide more information on the safety of this medicine.

United Kingdom

Yellow Card Scheme

Website:www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or

Apple App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website:www.hpra.ie

E-mail:medsafety@hpra.ie

Malta

ADR Reporting

Website:www.medicinesauthority.gov.mt/adrportal

5.

How to store Norvir

Keep this medicine out of the sight and reach of children.

Do not use Norvir powder for oral suspension after the expiry date on the sachet and carton. The

expiry date refers to the last day of the month.

Norvir powder for oral suspension should be stored below 30

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Norvir contains

The active substance is ritonavir. Each sachet of Norvir contains 100 mg ritonavir.

The other ingredients are copovidone; sorbitan laurate; silica, colloidal anhydrous.

What Norvir looks like and contents of the pack

Norvir powder for oral suspension comes in individual sachets containing 100 mg ritonavir.

30 sachets are packed in a carton together with 1 mixing cup and 2 oral dosing syringes.

Not all pack sizes may be marketed.

Norvir is also supplied as an oral solution containing 80 mg/ml of ritonavir and as a film-coated tablet

containing 100 mg ritonavir.

Marketing Authorisation Holder

AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany

Manufacturers

AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany

For any information about this medicine, please contact the local representative of the

Marketing Authorisation Holder:

Ireland

AbbVie Limited

Tel: +353 (0)1 4287900

Malta

V.J.Salomone Pharma Limited

Tel: +356 22983201

United Kingdom

AbbVie Ltd

Tel: +44 (0)1628 561090

This leaflet was last approved in 05/2018

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

Read the complete document

Object 1

Norvir Powder Oral Suspension

Summary of Product Characteristics Updated 06-Jun-2018 | AbbVie Limited

1. Name of the medicinal product

Norvir 100 mg powder for oral suspension

2. Qualitative and quantitative composition

Each sachet of powder for oral suspension contains 100 mg of ritonavir.

Excipients:

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for oral suspension.

Beige/pale yellow to yellow powder.

4. Clinical particulars

4.1 Therapeutic indications

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected

patients (adults and children of 2 years of age and older).

4.2 Posology and method of administration

Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection.

Posology

Ritonavir dosed as a pharmacokinetic enhancer

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of

Product Characteristics for the particular protease inhibitor must be consulted.

The following HIV-1 protease inhibitors have been approved for use with ritonavir as a pharmacokinetic

enhancer at the noted doses.

Adults

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.

Atazanavir 300 mg once daily with ritonavir 100 mg once daily.

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Lopinavir co-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg.

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients.

Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7

days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-naïve patients.

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. Tipranavir with ritonavir should not

be used in treatment-naïve patients.

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART)

experienced patients. Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in

some ART experienced patients. Refer to the darunavir Summary of Product Characteristics for

further information on once daily dosing in ART experienced patients.

Darunavir 800 mg once daily with ritonavir 100 mg once daily in ART-naïve patients.

Children and adolescents

Ritonavir is recommended for children 2 years of age and older. For further dosage recommendations,

refer to the product information of other protease inhibitors approved for co-administration with ritonavir.

Special populations

Renal impairment

As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as a

pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease inhibitor

with which it is co-administered. However, since the renal clearance of ritonavir is negligible, the

decrease in the total body clearance is not expected in patients with renal impairment. For specific dosing

information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of

the co-administered protease inhibitor.

Hepatic impairment

Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease

(see section 4.3). In the absence of pharmacokinetic studies in patients with stable severe hepatic

impairment (Child Pugh Grade C) without decompensation, caution should be exercised when ritonavir is

used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur. Specific

recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment

are dependent on the protease inhibitor with which it is co-administered. The SPC of the co-administered

PI should be reviewed for specific dosing information in this patient population.

Ritonavir dosed as an antiretroviral agent

Adults

The recommended dose of Norvir powder for oral suspension is 600 mg (six sachets) twice daily by

mouth and should be given with food.

Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.

Treatment should be initiated at 300 mg (three sachets) twice daily for a period of three days and

increased by 100 mg (one sachet) twice daily increments up to 600 mg twice daily over a period of no

longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.

Refer to Method of Administration section below and section 6.6 for details on preparing doses.

Children and adolescents (2 years of age and above)

The recommended dosage of Norvir powder for suspension in children is 350 mg/m

by mouth twice

daily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m

and increased at 2

to 3 day intervals by 50 mg/m

twice daily.

Paediatric dosage guidelines for Norvir powder for oral suspension (prepared as 100 mg/10 ml)*†

Body Surface

Area (m

2

)

Twice Daily Dose 250

mg/m

2

Twice Daily Dose 300

mg/m

2

Twice Daily Dose 350

mg/m

2

0.25

6.4 ml (62.5 mg)

7.6 ml (76 mg)

8.8 ml (88 mg)

0.50

12.6 ml (126 mg)

15.0 ml (150 mg)

17.6 ml (176 mg)

0.75

18.8 ml (188 mg)

22.6 ml (226 mg)

26.4 ml (262.5 mg)

1.00

25.0 ml (250 mg)

30.0 ml (300 mg)

35.0 ml (350 mg)

1.25

31.4 ml (312.5 mg)

37.6 ml (376 mg)

43.8 ml (438mg)

1.50

37.6 ml (376 mg)

45.0 ml (450 mg)

52.6 ml (526 mg)

*When mixed with 9.4 ml of liquid the concentration of the suspension is 10 mg/ml.

†In some instances, the volumes and/or doses have been adjusted to ensure the recommended final dose

and dosing volume.

Body surface area can be calculated with the following equation: BSA (m

) = √(Height (cm) X Weight

(kg) / 3600)

To calculate the volume to be administered (in ml) for intermediate body surface areas not included in the

above table, the body surface area should be multiplied by a factor of: 25 for a dose of 250 mg/m²; 30 for

300 mg/m²; and 35 for 350 mg/m².

Refer to Method of Administration section below and section 6.6 for details on preparing doses.

Special populations

Elderly

Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2).

Renal impairment

Currently, there are no data specific to this patient population and therefore specific dosage

recommendations cannot be made. The renal clearance of ritonavir is negligible; therefore, a decrease in

the total body clearance is not expected in patients with renal impairment. Because ritonavir is highly

protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Hepatic impairment

Ritonavir is principally metabolised and eliminated by the liver. Pharmacokinetic data indicate that no

dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2).

Ritonavir must not be given to patients with severe hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of Norvir in children aged below 2 years has not been established. Currently

available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Norvir powder for oral suspension is administered orally, poured on soft food (apple sauce or vanilla

pudding) or mixed with liquid (water, chocolate milk, or infant formula). For details on preparation and

administration of the Norvir powder for oral suspension, see section 6.6. Any mixing outside the

recommendations is the responsibility of the health care professional or the user.

Norvir powder for oral suspension should be taken with food. The bitter aftertaste of Norvir powder for

oral suspension may be lessened if peanut butter, hazelnut chocolate spread, or black currant syrup are

taken immediately after dose administration.

The prescribed dose of Norvir powder for oral suspension can be administered via a feeding tube after

being mixed with water as detailed in section 6.6. Follow the instructions for the feeding tube to

administer the medicine.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product

Characteristics of the co-administered protease inhibitor for contraindications.

Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients with

decompensated liver disease.

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and

CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with

ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to inhibit

metabolism of the co-administered medicinal product, resulting in increased exposure to the co-

administered medicinal product and risk of clinically significant adverse effects.

The enzyme-modulating effect of ritonavir may be dose dependent. For some products, contraindications

may be more relevant when ritonavir is used as an antiretroviral agent than when ritonavir is used as a

pharmacokinetic enhancer (e.g. rifabutin and voriconazole):

Medicinal Product Class Medicinal Products

within Class

Rationale

Concomitant medicinal product levels increased or decreased

-Adrenoreceptor

Antagonist

Alfuzosin

Increased plasma concentrations of alfuzosin which

may lead to severe hypotension (see section 4.5).

Analgesics

Pethidine, piroxicam,

propoxyphne

Increased plasma concentrations of norpethidine,

piroxicam and propoxyphene. Thereby, increasing

the risk of serious respiratory depression or

haematologic abnormalities, or other serious adverse

effects from these agents.

Antianginal

Ranolazine

Increased plasma concentrations of ranolazine which

may increase the potential for serious and/or life-

threatening reactions (see section 4.5).

Anticancer

Venetoclax

Increased plasma concentrations of venetoclax.

Increased risk of tumor lysis syndrome at the dose

initiation and during the dose-titration phase (see

section 4.5).

Antiarrhythmics

Amiodarone, bepridil,

dronedarone, encainide,

flecanide, propafenone,

quinidine

Increased plasma concentrations of amiodarone,

bepridil, dronedarone, encainide, flecanide,

propafenone, quinidine. Thereby, increasing the risk

of arrhythmias or other serious adverse reactions

from these agents.

Antibiotic

Fusidic Acid

Increased plasma concentrations of fusidic acid and

ritonavir.

Antifungal

Voriconazole

Concomitant use of ritonavir (400 mg twice daily

and more) and voriconazole is contraindicated due to

a reduction in voriconazole plasma concentrations

and possible loss of effect (see section 4.5).

Anti-gout

Colchicine

Potential for serious and/or life-threatening reactions

in patients with renal and/or hepatic impairment (see

sections 4.4 and 4.5).

Antihistamines

Astemizole, terfenadine

Increased plasma concentrations of astemizole and

terfenadine. Thereby, increasing the risk of serious

arrhythmias from these agents.

Antimycobacterial

Rifabutin

Concomitant use of ritonavir (500 mg twice daily)

dosed as an antiretroviral agent and rifabutin due to

an increase of rifabutin serum concentrations and

risk of adverse events including uveitis (see section

4.4). Recommendations regarding use of ritonavir

dosed as a pharmacokinetic enhancer with rifabutin

are noted in section 4.5.

Antipsychotics/

Neuroleptics

Lurasidone

Increased plasma concentrations of lurasidone which

may increase the potential for serious and/or life-

threatening reactions (see section 4.5).

Clozapine, pimozide

Increased plasma concentrations of clozapine and

pimozide. Thereby, increasing the risk of serious

haematologic abnormalities, or other serious adverse

effects from these agents.

Quetiapine

Increased plasma concentrations of quetiapine which

may lead to coma. The concomitant administration

with quetiapine is contraindicated (see section 4.5).

Ergot Derivatives

Dihydroergotamine,

Increased plasma concentrations of ergot derivatives

ergonovine, ergotamine,

methylergonovine

leading to acute ergot toxicity, including vasospasm

and ischaemia.

GI motility agent

Cisapride

Increased plasma concentrations of cisapride.

Thereby, increasing the risk of serious arrhythmias

from this agent.

HMG Co-A Reductase

Inhibitor

Lovastatin, simvastatin

Increased plasma concentrations of lovastatin and

simvastatin; thereby, increasing the risk of myopathy

including rhabdomyolysis (see section 4.5).

PDE5 inhibitors

Avanafil

Increased plasma concentrations of avanafil (see

section 4.4. and 4.5).

Sildenafil

Contraindicated when used for the treatment of

pulmonary arterial hypertension (PAH) only.

Increased plasma concentrations of sildenafil.

Thereby, increasing the potential for sildenafil-

associated adverse events (which include

hypotension and syncope). See section 4.4 and

section 4.5 for co-administration of sildenafil in

patients with erectile dysfunction.

Vardenafil

Increased plasma concentrations of vardenafil (see

section 4.4. and 4.5).

Sedatives/hypnotics

Clorazepate, diazepam,

estazolam, flurazepam,

oral midazolam and

triazolam

Increased plasma concentrations of clorazepate,

diazepam, estazolam, flurazepam, oral midazolam

and triazolam. Thereby, increasing the risk of

extreme sedation and respiratory depression from

these agents. (For caution on parenterally

administered midazolam, see section 4.5).

Ritonavir medicinal product level decreased

Herbal Preparation

St. John's wort

Herbal preparations containing St John's wort

(Hypericum perforatum) due to the risk of decreased

plasma concentrations and reduced clinical effects of

ritonavir (see section 4.5).

4.4 Special warnings and precautions for use

Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving ritonavir or any other antiretroviral

therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the

risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should

be taken in accordance with national guidelines.

When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and

precautions relevant to that particular PI should be considered, therefore the Summary of Product

Characteristics for the particular PI must be consulted.

Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

Patients with chronic diarrhoea or malabsorption

Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea

during treatment with ritonavir may compromise the absorption and efficacy (due to decreased

compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or

diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor

renal function in patients with renal function impairment.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and

haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients

additional factor VIII was given. In more than a half of the reported cases, treatment with protease

inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has

been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should,

therefore, be made aware of the possibility of increased bleeding.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.

Such changes may in part be linked to disease control and life style. For lipids, there is in some cases

evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any

particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV

treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or

abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of

pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Norvir

therapy should be discontinued if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination

antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic

pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such

reactions have been observed within the first few weeks or months of initiation of CART. Relevant

examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and

Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment

instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of

immune reconstitution; however, the reported time to onset is more variable and can occur many months

after initiation of treatment.

Liver disease

Ritonavir should not be given to patients with decompensated liver disease (see section 4.2). Patients with

chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for

severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for

hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency

of liver function abnormalities during combination antiretroviral therapy and should be monitored

according to standard practice. If there is evidence of worsening liver disease in such patients,

interruption or discontinuation of treatment must be considered.

Renal disease

Since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not expected

in patients with renal impairment (see also section 4.2).

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy

(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical

practice (see section 4.8).

Medication error

Special attention should be given to the accurate calculation of the dose of Norvir, transcription of the

medication order, dispensing information and dosing instructions to minimise the risk for medication

errors and underdose. This is especially important for infants and young children.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol

consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been

reported in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral

therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and

pain, joint stiffness or difficulty in movement.

PR interval prolongation

Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy

adult subjects. Rare reports of 2

or 3

degree atrioventricular block in patients with underlying

structural heart disease and pre-existing conduction system abnormalities or in patients receiving

medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have been

reported in patients receiving ritonavir. Norvir should be used with caution in such patients (see section

5.1).

Interactions with other medicinal products

Ritonavir dosed as an antiretroviral agent

The following warnings and precautions should be considered when ritonavir is used as an antiretroviral

agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg level it cannot be

assumed that the following warnings and precautions will also apply. When ritonavir is used as a

pharmacokinetic enhancer, full details on the warnings and precautions relevant to that particular PI must

be considered, therefore the Summary of Product Characteristics, section 4.4, for the particular PI must be

consulted to determine if the information below is applicable.

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile

dysfunction in patients receiving ritonavir. Co-administration of ritonavir with these medicinal products is

expected to substantially increase their concentrations and may result in associated adverse reactions such

as hypotension and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil with

ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil with ritonavir is

contraindicated in pulmonary arterial hypertension patients (see section 4.3).

HMG-CoA reductase inhibitors

The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for

metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is not recommended due to

an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced

doses should be considered if ritonavir is used concurrently with atorvastatin, which is metabolised to a

lesser extent by CYP3A. While rosuvastatin elimination is not dependent on CYP3A, an elevation of

rosuvastatin exposure has been reported with ritonavir co-administration. The mechanism of this

interaction is not clear, but may be the result of transporter inhibition. When used with ritonavir dosed as

a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses of atorvastatin or rosuvastatin

should be administered. The metabolism of pravastatin and fluvastatin is not dependent of CYP3A, and

interactions are not expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is

indicated, pravastatin or fluvastatin is recommended (see section 4.5).

Colchicine

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and

strong inhibitors of CYP3A like ritonavir (see sections 4.3 and 4.5).

Digoxin

Particular caution should be used when prescribing ritonavir in patients taking digoxin since co-

administration of ritonavir with digoxin is expected to increase digoxin levels. The increased digoxin

levels may lessen over time (see section 4.5).

In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be

reduced to one-half of the patients' normal dose and patient need to be followed more closely than usual

for several weeks after initiating co-administration of ritonavir and digoxin.

In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced

more gradually than usual. Digoxin levels should be monitored more intensively than usual during this

period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and digoxin

level findings.

Ethinyl estradiol

Barrier or other non-hormonal methods of contraception should be considered when administering

ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change the uterine

bleeding profile when co-administered with estradiol-containing contraceptives.

Glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is

not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid

effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Trazodone

Particular caution should be used when prescribing ritonavir in patients using trazodone. Trazodone is a

CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone levels. Adverse

reactions of nausea, dizziness, hypotension and syncope have been observed in single dose interaction

studies in healthy volunteers (see section 4.5)

Rivaroxaban

It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased

bleeding (see section 4.5).

Riociguat

The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure (see

section 4.5).

Vorapaxar

The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure (see

section 4.5).

Bedaquiline

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could

potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of

bedaquiline with ritonavir should be avoided. However, if the benefit outweighs the risk, co-

administration of bedaquiline with ritonavir must be done with caution. More frequent electrocardiogram

monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline

Summary of Product Characteristics).

Delamanid

Co-administration of delamanid with a strong inhibitor of CYP3A (ritonavir) may increase exposure to

delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration

of delamanid with ritonavir is considered necessary, very frequent ECG monitoring throughout the full

delamanid treatment period is recommended (see section 4.5 and refer to the delamanid Summary of

Product Characteristics).

Ritonavir dosed as a pharmacokinetic enhancer

The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are

dependent on the specific co-administered protease inhibitor.

For a description of the mechanisms and potential mechanisms contributing to the interaction profile of

the PIs, see section 4.5. Please also review the Summary of Product Characteristics for the particular

boosted PI.

Saquinavir

Doses of ritonavir higher than 100 mg twice daily should not be used. Higher doses of ritonavir have been

shown to be associated with an increased incidence of adverse reactions. Co-administration of saquinavir

and ritonavir has led to severe adverse reactions, mainly diabetic ketoacidosis and liver disorders,

especially in patients with pre-existing liver disease.

Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe hepatotoxicity

(presenting as increased hepatic transaminases) if the three medicines are given together (see section 4.5).

Tipranavir

Co-administration of tipranavir with 200 mg of ritonavir has been associated with reports of clinical

hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients

with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of

hepatotoxicity.

Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy

profile of the combination.

Fosamprenavir

Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice daily has not been

clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination

and therefore is not recommended.

Atazanavir

Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been

clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac

effects, hyperbilirubinemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-

administered with efavirenz, a dose increase of ritonavir to 200mg once daily could be considered. In this

instance, close clinical monitoring is warranted. Refer to the Summary of Product Characteristics for

atazanavir for further details.

4.5 Interaction with other medicinal products and other forms of interaction

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with

the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products

primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal

product, which could increase or prolong its therapeutic and adverse effects. For selected medicinal

products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time.

Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect

of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g.

digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal products” below).

Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19

thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and

may result in decreased systemic exposure to such medicinal products, which could decease or shorten

their therapeutic effect.

Important information regarding medicinal product interactions when ritonavir is used as a

pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-

administered protease inhibitor.

Medicinal products that affect ritonavir levels

Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John's

wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by

St John's wort. Herbal preparations containing St John's wort must not be used in combination with

ritonavir. If a patient is already taking St John's wort, St John's wort should be stopped and if possible

check viral levels. Ritonavir levels may increase on stopping St John's wort. The dose of ritonavir may

need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St

John's wort (see section 4.3).

Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. delavirdine,

efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinal product interaction

tables below.

Medicinal product that are affected by the use of ritonavir

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors

and other non-antiretroviral medicinal products are listed in the tables below.

Medicinal Product Interactions – Ritonavir with Protease Inhibitors

Co-administered

Medicinal

Product

Dose of Co-administered

Medicinal Product (mg)

Dose of NORVIR

(mg)

Medicinal

Product

Assessed

AUC

C

min

Amprenavir

600 q12h

100 q12h

Amprenavir

↑ 64%

↑ 5 fold

Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition.

Clinical trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with

ritonavir 100 mg twice daily. Norvir oral solution should not be co-administered with

amprenavir oral solution to children due to the risk of toxicity from excipients in the

two formulations. For further information, physicians should refer to the Summary of

Product Characteristics for amprenavir.

Atazanavir

300 q24h

100 q24h

Atazanavir

↑ 86%

↑ 11

fold

Atazanavir

↑ 2 fold

↑ 3-7

fold

Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition.

Clinical trials confirmed the safety and efficacy of 300 mg atazanavir once daily with

ritonavir 100 mg once daily in treatment experienced patients. For further information,

physicians should refer to the Summary of Product Characteristics for atazanavir.

Darunavir

600, single

100 q12h

Darunavir

↑ 14 fold

Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition.

Darunavir must be given with ritonavir to ensure its therapeutic effect. Ritonavir doses

higher than 100 mg twice daily have not been studied with darunavir. For further

information, refer to the Summary of Product Characteristics for darunavir.

Fosamprenavir

700 q12h

100 q12h

Amprenavir

↑ 2.4 fold

↑ 11

fold

Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of

CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its

therapeutic effect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700

mg twice daily with ritonavir 100 mg twice daily. Ritonavir doses higher than 100 mg

twice daily have not been studied with fosamprenavir. For further information,

physicians should refer to the Summary of Product Characteristics for fosamprenavir.

Indinavir

800 q12h

100 q12h

Indinavir

↑ 178%

Ritonavir

↑ 72%

400 q12h

400 q12h

Indinavir

↑ 4 fold

Ritonavir

Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition.

Appropriate doses for this combination, with respect to efficacy and safety, have not

been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement

is achieved with doses higher than 100 mg twice daily. In cases of co-administration of

ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted

as the risk of nephrolithiasis may be increased.

Nelfinavir

1250 q12h

100 q12h

Nelfinavir

↑ 20to39% ND

750, single

500 q12h

Nelfinavir

↑ 152%

Ritonavir

Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition.

Appropriate doses for this combination, with respect to efficacy and safety, have not

been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement

is achieved with doses higher than 100 mg twice daily.

Saquinavir

1000 q12h

100 q12h

Saquinavir

↑ 15-fold

↑ 5-fold

Ritonavir

400 q12h

400 q12h

Saquinavir

↑ 17-fold

Ritonavir

Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition.

Saquinavir should only be given in combination with ritonavir. Ritonavir 100 mg twice

daily with saquinavir 1000 mg twice daily provides saquinavir systemic exposure over

24 hours similar to or greater than those achieved with saquinavir 1200 mg three times

daily without ritonavir.

In a clinical study investigating the interaction of rifampicin 600 mg once daily and

saquinavir 1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe

hepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit of

normal after 1 to 5 days of co-administration was noted. Due to the risk of severe

hepatoxicity, saquinavir/ritonavir should not be given together with rifampicin.

For further information, physicians should refer to the Summary of Product

Characteristics for saquinavir.

Tipranavir

500 q12h

200 q12h

Tipranavir

↑ 11 fold

↑ 29

fold

Ritonavir

↓ 40%

Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition.

Tipranavir must be given with low dose ritonavir to ensure its therapeutic effect. Doses

of ritonavir less than 200 mg twice daily should not be used with tipranavir as they

might alter the efficacy of the combination. For further information, physicians should

refer to the Summary of Product Characteristics for tipranavir.

ND: Not determined.

1. Based on cross-study comparison to 1200 mg amprenavir twice daily alone.

2. Based on cross-study comparison to 400 mg atazanavir once daily alone.

3. Based on cross-study comparison to 800 mg indinavir three times daily alone.

4. Based on cross-study comparison to 600 mg saquinavir three times daily alone.

Medicinal product interactions – Ritonavir with antiretroviral agents other than protease inhibitors

Co-administered

Medicinal

Product

Dose of Co-

administered

Medicinal

Product (mg)

Dose of

NORVIR (mg)

Medicinal Product

Assessed

AUC

C

min

Didanosine

200 q12h

600 q12h 2 h

later

Didanosine

↓ 13%

As ritonavir is recommended to be taken with food and didanosine should be taken on

an empty stomach, dosing should be separated by 2.5 h. Dose alterations should not be

necessary.

Delavirdine

400 q8h

600 q12h

Delavirdine

Ritonavir

↑ 50%

↑ 75%

Based on comparison to historical data, the pharmacokinetics of delavirdine did not

appear to be affected by ritonavir. When used in combination with delavirdine, dose

reduction of ritonavir may be considered.

Efavirenz

600 q24h

500 q12h

Efavirenz

↑ 21%

Ritonavir

↑ 17%

A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) and

laboratory abnormalities (elevated liver enzymes) have been observed when efavirenz is

co-administered with ritonavir dosed as an antiretroviral agent.

Maraviroc

100 q12h

100 q12h

Maraviroc

↑161%

↑28%

Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition.

Maraviroc may be given with ritonavir to increase the maraviroc exposure. For further

information, refer to the Summary of Product Characteristics for maraviroc.

Nevirapine

200 q12h

600 q12h

Nevirapine

Ritonavir

Co-administration of ritonavir with nevirapine does not lead to clinically relevant

changes in the pharmacokinetics of either nevirapine or ritonavir.

Raltegravir

400 single

100 q12h

Raltegravir

↓ 16%

↓ 1%

Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir

levels

Zidovudine

200 q8h

300 q6h

Zidovudine

↓ 25%

Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased

levels of zidovudine. Dose alterations should not be necessary.

ND: Not determined

1. Based on parallel group comparison.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered

Medicinal Products

Dose of Co-

administered

Medicinal

Products (mg)

Dose of NORVIR

(mg)

Effect on Co-

administered

Medicinal

Products AUC

Effect on Co-

administered

Medicinal

Products C

max

Alpha

1

-Adrenoreceptor Antagonist

Alfuzosin

Ritonavir co-administration is likely to result in increased plasma concentrations

of alfuzosin and is therefore contraindicated (see section 4.3).

Amphetamine Derivatives

Amphetamine

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a

result is expected to increase concentrations of amphetamine and its derivatives.

Careful monitoring of therapeutic and adverse effects is recommended when

these medicines are concomitantly administered with antiretroviral doses of

ritonavir (see section 4.4).

Analgesics

Buprenorphine

16 q24h

100 q12h

↑ 57%

↑ 77%

Norbuprenorphine

↑ 33%

↑ 108%

Glucuronide metabolites

The increases of plasma levels of buprenorphine and its active metabolite did not

lead to clinically significant pharmacodynamic changes in a population of opioid

tolerant patients. Adjustment to the dose of buprenorphine or ritonavir may

therefore not be necessary when the two are dosed together. When ritonavir is

used in combination with another protease inhibitor and buprenorphine, the SPC

of the co-administered protease inhibitor should be reviewed for specific dosing

information.

Pethidine, piroxicam,

propoxyphene

Ritonavir co-administration is likely to result in increased plasma concentrations

of pethidine, piroxicam, and propoxyphene and is therefore contraindicated (see

section 4.3).

Fentanyl

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A4 and as a result is expected to increase the plasma

concentrations of fentanyl. Careful monitoring of therapeutic and adverse effects

(including respiratory depression) is recommended when fentanyl is

concomitantly administered with ritonavir.

Methadone

5, single dose

500 q12h,

↓ 36%

↓ 38%

Increased methadone dose may be necessary when concomitantly administered

with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

due to induction of glucuronidation. Dose adjustment should be considered based

on the patient's clinical response to methadone therapy.

Morphine

Morphine levels may be decreased due to induction of glucuronidation by co-

administered ritonavir dosed as an antiretroviral agent or as a pharmacokinetic

enhancer.

Antianginal

Ranolazine

Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected

to increase. The concomitant administration with ranolazine is contraindicated

(see section 4.3).

Antiarrthymics

Amiodarone, bepridil,

dronedarone, encainide,

flecainide, propafenone,

quinidine

Ritonavir co-administration is likely to result in increased plasma concentrations

of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and

quinidine and is therefore contraindicated (see section 4.3).

Digoxin

0.5 single IV dose

300 q12h, 3 days

↑ 86%

0.4 single oral dose 200 q12h, 13 days

↑ 22%

This interaction may be due to modification of P-glycoprotein mediated digoxin

efflux by ritonavir dosed as an antriretroviral agent or as a pharmacokinetic

enhancer. Increased digoxin levels observed in patients receiving ritonavir may

lessen over time as induction develops (see section 4.4).

Antiasthmatic

Theophylline

3 mg/kg q8h

500 q12h

↓ 43%

↓ 32%

An increased dose of theophylline may be required when co-administered with

ritonavir, due to induction of CYP1A2.

Anticancer agents

Afatinib

20 mg, single dose

40 mg, single dose

40 mg, single dose

200 q12h/1h before

200 q12h/ co-

administered

200 q12h/6h after

↑ 48%

↑ 19%

↑ 11%

↑ 39%

↑ 4%

↑ 5%

Serum concentrations may be increased due to Breast Cancer Resistance Protein

(BCRP) and acute P-gp inhibition by ritonavir. The extent of increase in AUC

and C

depends on the timing of ritonavir administration. Caution should be

exercised in administering afatinib with Norvir (refer to the afatinib SmPC).

Monitor for ADRs related to afatinib.

Ceritinib

Serum concentrations may be increased due to CYP3A and P-gp inhibition by

ritonavir. Caution should be exercised in administering ceritinib with Norvir.

Refer to the ceritinib SmPC for dosage adjustment recommendations. Monitor

for ADRs related to ceritinib.

Dasatinib, nilotinib,

vincristine, vinblastine

Serum concentrations may be increased when co-administered with ritonavir

resulting in the potential for increased incidence of adverse events.

Venetoclax

Serum concentrations may be increased due to CYP3A inhibition by ritonavir,

resulting in increased risk of tumor lysis syndrome at the dose initiation and

during the ramp-up phase (see section 4.3 and refer to the venetoclax SmPC).

For patients who have completed the ramp-up phase and are on a steady daily

dose of venetoclax, reduce the venetoclax dose by at least 75% when used with

strong CYP3A inhibitors (refer to the venetoclax SmPC for dosing instructions).

Anticoagulants

Rivaroxaban

10, single dose

600 q12h

↑ 153%

↑ 55%

Inhibition of CYP3A and P-gp lead to increased plasma levels and

pharmacodynamic effects of rivaroxaban which may lead to an increased

bleeding risk. Therefore, the use of ritonavir is not recommended in patients

receiving rivaroxaban.

Vorapaxar

Serum concentrations may be increased due to CYP3A inhibition by ritonavir.

The co-administration of vorapaxar with Norvir is not recommended (see section

4.4 and refer to the vorapaxar SmPC).

Warfarin

S-Warfarin

R-Warfarin

5, single dose

400 q12h

↑ 9%

↓ 33%

↓ 9%

Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-warfarin while

little pharmacokinetic effect is noted on S- warfarin when co-administered with

ritonavir. Decreased R-warfarin levels may lead to reduced anticoagulation,

therefore it is recommended that anticoagulation parameters are monitored when

warfarin is co-administered with ritonavir dosed as an antiretroviral agent or as a

pharmacokinetic enhancer.

Anticonvulsants

Carbamazepine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A4 and as a result is expected to increase the plasma

concentrations of carbamazepine. Careful monitoring of therapeutic and adverse

effects is recommended when carbamazepine is concomitantly administered with

ritonavir.

Divalproex, lamotrigine,

phenytoin

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

induces oxidation by CYP2C9 and glucuronidation and as a result is expected to

decrease the plasma concentrations of anticonvulsants. Careful monitoring of

serum levels or therapeutic effects is recommended when these medicines are

concomitantly administered with ritonavir. Phenytoin may decrease serum levels

of ritonavir.

Antidepressants

Amitriptyline,

fluoxetine, imipramine,

nortriptyline, paroxetine,

sertraline

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a

result is expected to increase concentrations of imipramine, amitriptyline,

nortriptyline, fluoxetine, paroxetine or sertraline. Careful monitoring of

therapeutic and adverse effects is recommended when these medicines are

concomitantly administered with antiretroviral doses of ritonavir (see section

4.4).

Desipramine

100, single oral

dose

500 q12h

↑ 145%

↑ 22%

The AUC and C

of the 2-hydroxy metabolite were decreased 15 and 67%,

respectively. Dosage reduction of desipramine is recommended when co-

administered with ritonavir dosed as an antiretroviral agent.

Trazodone

50, single dose

200 q12h

↑ 2.4-fold

↑ 34%

An increase in the incidence in trazodone-related adverse reactions was noted

when co-administered with ritonavir dosed as an antiretroviral agent or as a

pharmacokinetic enhancer. If trazodone is co-administered with ritonavir, the

combination should be used with caution, initiating trazodone at the lowest

dosage and monitoring for clinical response and tolerability.

Anti-gout treatments

Colchicine

Concentrations of colchicine are expected to increase when coadministered with

ritonavir.

Life-threatening and fatal drug interactions have been reported in patients treated

with colchicine and ritonavir (CYP3A4 and P-gp inhibition) in patients with

renal and/or hepatic impairment (see sections 4.3 and 4.4). Refer to the

colchicine prescribing information.

Antihistamines

Astemizole, terfenadine

Ritonavir co-administration is likely to result in increased plasma concentrations

of astemizole and terfenadine and is therefore contraindicated (see section 4.3).

Fexofenadine

Ritonavir may modify P-glycoprotein mediated fexofenadine efflux when dosed

as an antriretroviral agent or as a pharmacokinetic enhancer resulting in

increased concentrations of fexofenadine. Increased fexofenadine levels may

lessen over time as induction develops.

Loratadine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A and as a result is expected to increase the plasma concentrations

of loratadine. Careful monitoring of therapeutic and adverse effects is

recommended when loratidine is concomitantly administered with ritonavir.

Anti-infectives

Fusidic Acid

Ritonavir co-administration is likely to result in increased plasma concentrations

of both fusidic acid and ritonavir and is therefore contraindicated (see section

4.3).

Rifabutin

25-O-desacetyl rifabutin

metabolite

150 daily

500 q12h,

↑ 4-fold

↑ 38-fold

↑ 2.5-fold

↑ 16-fold

Due to the large increase in rifabutin AUC, the concomitant use of rifabutin with

ritonavir dosed as an antiretroviral agent is contraindicated (see section 4.3).

The reduction of the rifabutin dose to 150 mg 3 times per week may be indicated

for select PIs when co-administered with ritonavir as a pharmacokinetic

enhancer. The Summary of Product Characteristics of the co-administered

protease inhibitor should be consulted for specific recommendations.

Consideration should be given to official guidance on the appropriate treatment

of tuberculosis in HIV-infected patients.

Rifampicin

Although rifampicin may induce metabolism of ritonavir, limited data indicate

that when high doses of ritonavir (600 mg twice daily) is co-administered with

rifampicin, the additional inducing effect of rifampicin (next to that of ritonavir

itself) is small and may have no clinical relevant effect on ritonavir levels in

high-dose ritonavir therapy. The effect of ritonavir on rifampicin is not known.

Voriconazole

200 q12h

400 q12h

↓ 82%

↓ 66%

200 q12h

100 q12h

↓ 39%

↓ 24%

Concomitant use of ritonavir dosed as an antiretroviral agent and voriconazole is

contraindicated due to reduction in voriconazole concentrations (see section

4.3). Co-administration of voriconazole and ritonavir dosed as a pharmacokinetic

enhancer should be avoided, unless an assessment of the benefit/risk to the

patient justifies the use of voriconazole.

Atovaquone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

induces glucuronidation and as a result is expected to decrease the plasma

concentrations of atovaquone. Careful monitoring of serum levels or therapeutic

effects is recommended when atovaquone is concomitantly administered with

ritonavir.

Bedaquiline

No interaction study is available with ritonavir only. In an interaction study of

single-dose bedaquiline and multiple dose lopinavir/ritonavir, the AUC of

bedaquiline was increased by 22%. This increase is likely due to ritonavir and a

more pronounced effect may be observed during prolonged co-administration.

Due to the risk of bedaquiline related adverse events, co-administration should

be avoided. If the benefit outweighs the risk, co-administration of bedaquiline

with ritonavir must be done with caution. More frequent electrocardiogram

monitoring and monitoring of transaminases is recommended (see section 4.4

and refer to the bedaquiline Summary of Product Characteristics).

Clarithromycin

14-OH clarithromycin

metabolite

500 q12h

200 q8h

↑ 77%

↓ 100%

↑ 31%

↓ 99%

Due to the large therapeutic window of clarithromycin no dose reduction should

be necessary in patients with normal renal function. Clarithromycin doses greater

than 1 g per day should not be co-administered with ritonavir dosed as an

antiretroviral agent or as a pharmacokinetic enhancer. For patients with renal

impairment, a clarithromycin dose reduction should be considered: for patients

with creatinine clearance of 30 to 60 ml/min the dose should be reduced by 50%,

for patients with creatinine clearance less than 30 ml/min the dose should be

reduced by 75%.

Delamanid

No interaction study is available with ritonavir only. In a healthy volunteer drug

interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir

400/100 mg twice daily for 14 days, the exposure of the delamanid metabolite

DM-6705 was 30% increased. Due to the risk of QTc prolongation associated

with DM-6705, if co-administration of delamanid with ritonavir is considered

necessary, very frequent ECG monitoring throughout the full delamanid

treatment period is recommended (see section 4.4 and refer to the delamanid

Summary of Product Characteristics).

Erythromycin,

itraconazole

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A4 and as a result is expected to increase the plasma

concentrations of erythromycin and itraconazole. Careful monitoring of

therapeutic and adverse effects is recommended when erythromycin or

itraconazole is used concomitantly administered with ritonavir.

Ketoconazole

200 daily

500 q12h

↑ 3.4-fold

↑ 55%

Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due to an

increased incidence of gastrointestinal and hepatic adverse reactions, a dose

reduction of ketoconazole should be considered when co-administered with

ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Sulfamethoxazole/Trime

thoprim²

800/160, single

dose

500 q12h

↓ 20% / ↑ 20%

Dose alteration of sulfamethoxazole/trimethoprim during concomitant ritonavir

therapy should not be necessary.

Antipsychotics/Neuroleptics

Clozapine, pimozide

Ritonavir co-administration is likely to result in increased plasma concentrations

of clozapine or pimozide and is therefore contraindicated (see section 4.3).

Haloperidol, risperidone,

thioridazine

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a

result is expected to increase concentrations of haloperidol, risperidone and

thioridazine. Careful monitoring of therapeutic and adverse effects is

recommended when these medicines are concomitantly administered with

antiretroviral doses of ritonavir.

Lurasidone

Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected

to increase. The concomitant administration with lurasidone is contraindicated

(see section 4.3).

Quetiapine

Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected

to increase. Concomitant administration of Norvir and quetiapine is

contraindicated as it may increase quetiapine-related toxicity (see section 4.3).

β2-agonist (long acting)

Salmeterol

Ritonavir inhibits CYP3A4 and as a result a pronounced increase in the plasma

concentrations of salmeterol is expected. Therefore concomitant use is not

recommended.

Calcium channel antagonists

Amlodipine, diltiazem,

nifedipine

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A4 and as a result is expected to increase the plasma

concentrations of calcium channel antagonists. Careful monitoring of therapeutic

and adverse effects is recommended when these medicines are concomitantly

administered with ritonavir.

Endothelin antagonists

Bosentan

Co-administration of bosentan and ritonavir may increase steady state bosentan

maximum concentrations (C

) and area under the curve (AUC)

Riociguat

Serum concentrations may be increased due to CYP3A and P-gp inhibition by

ritonavir. The co-administration of riociguat with Norvir is not recommended

(see section 4.4 and refer to riociguat SmPC).

Ergot Derivatives

Dihydroergotamine,

ergonovine, ergotamine,

methylergonovine

Ritonavir co-administration is likely to result in increased plasma concentrations

of ergot derivatives and is therefore contraindicated (see section 4.3).

GI motility agent

Cisapride

Ritonavir co-administration is likely to result in increased plasma concentrations

of cisapride and is therefore contraindicated (see section 4.3).

HCV Protease Inhibitor

Simeprevir

200 qd

100 q12h

↑ 7.2-fold

↑ 4.7-fold

Ritonavir increases plasma concentrations of simeprevir as a result of CYP3A4

inhibition. It is not recommended to co-administer ritonavir with simeprevir.

HMG Co-A Reductase Inhibitors

Atorvastatin,

Fluvastatin, Lovastatin,

Pravastatin,

Rosuvastatin,

Simvastatin

HMG-CoA reductase inhibitors which are highly dependent on CYP3A

metabolism, such as lovastatin and simvastatin, are expected to have markedly

increased plasma concentrations when co-administered with ritonavir dosed as

an antiretroviral agent or as a pharmacokinetic enhancer. Since increased

concentrations of lovastatin and simvastatin may predispose patients to

myopathies, including rhabdomyolysis, the combination of these medicinal

products with ritonavir is contraindicated (see section 4.3). Atorvastatin is less

dependent on CYP3A for metabolism. While rosuvastatin elimination is not

dependent on CYP3A, an elevation of rosuvastatin exposure has been reported

with ritonavir co-administration. The mechanism of this interaction is not clear,

but may be the result of transporter inhibition. When used with ritonavir dosed as

a pharmacokinetic enhancer or as an antiretroviral agent, the lowest possible

doses of atorvastatin or rosuvastatin should be administered. The metabolism of

pravastatin and fluvastatin is not dependent on CYP3A, and interactions are not

expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is

indicated, pravastatin or fluvastatin is recommended.

Hormonal contraceptive

Ethinyl estradiol

50 µg, single dose

500 q12h

↓ 40%

↓ 32%

Due to reductions in ethinyl estradiol concentrations, barrier or other non-

hormonal methods of contraception should be considered with concomitant

ritonavir use when dosed as an antiretroviral agent or as a pharmacokinetic

enhancer. Ritonavir is likely to change the uterine bleeding profile and reduce

the effectiveness of estradiol-containing contraceptives (see section 4.4).

Immunosupressants

Cyclosporine,

tacrolimus, everolimus

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A4 and as a result is expected to increase the plasma

concentrations of cyclosporine, tacrolimus or everolimus. Careful monitoring of

therapeutic and adverse effects is recommended when these medicines are

concomitantly administered with ritonavir.

Phosphodiesterase (PDE5) inhibitors

Avanafil

50, single dose

600 q12h

↑ 13-fold

↑ 2.4-fold

Concomitant use of avanafil with ritonavir is contraindicated (see section 4.3).

Sildenafil

100, single dose

500 q12h

↑ 11-fold

↑ 4-fold

Concomitant use of sildenafil for the treatment of erectile dysfunction, with

ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

should be used with caution and in no instance should sildenafil doses exceed 25

mg in 48 hours (see also section 4.4). Concomitant use of sildenafil with

ritonavir is contraindicated in pulmonary arterial hypertension patients (see

section 4.3).

Tadalafil

20, single dose

200 q12h

↑ 124%

The concomitant use of tadalafil for the treatment of erectile dysfunction with

ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer

should be with caution at reduced doses of no more than 10 mg tadalafil every 72

hours with increased monitoring for adverse reactions (see section 4.4).

When tadalafil is used concurrently with ritonavir in patients with pulmonary

arterial hypertension, refer to the tadalafil Summary of Product Characteristics.

Vardenafil

5, single dose

600 q12h

↑ 49-fold

↑ 13-fold

Concomitant use of vardenafil with ritonavir is contraindicated (see section 4.3).

Sedatives/hynoptics

Clorazepate, diazepam,

estazolam, flurazepam,

oral and parenteral

midazolam

Ritonavir co-administration is likely to result in increased plasma concentrations

of clorazepate, diazepam, estazolam and flurazepam and is therefore

contraindicated (see section 4.3).

Midazolam is extensively metabolised by CYP3A4. Co-administration with

Norvir may cause a large increase in the concentration of this benzodiazepine.

No medicinal product interaction study has been performed for the co-

administration of Norvir with benzodiazepines. Based on data for other CYP3A4

inhibitors, plasma concentrations of midazolam are expected to be significantly

higher when midazolam is given orally. Therefore, Norvir should not be co-

administered with orally administered midazolam (see section 4.3), whereas

caution should be used with co-administration of Norvir and parenteral

midazolam. Data from concomitant use of parenteral midazolam with other

protease inhibitors suggest a possible 3 – 4 fold increase in midazolam plasma

levels. If Norvir is co-administered with parenteral midazolam, it should be done

in an intensive care unit (ICU) or similar setting which ensures close clinical

monitoring and appropriate medical management in case of respiratory

depression and/or prolonged sedation. Dosage adjustment for midazolam should

be considered, especially if more than a single dose of midazolam is

administered.

Triazolam

0.125, single dose

200, 4 doses

↑ > 20 fold

↑ 87%

Ritonavir co-administration is likely to result in increased plasma concentrations

of triazolam and is therefore contraindicated (see section 4.3).

Pethidine

Norpethidine metabolite

50, oral single dose 500 q12h

↓ 62%

↑ 47%

↓ 59%

↑ 87%

The use of pethidine and ritonavir is contraindicated due to the increased

concentrations of the metabolite, norpethidine, which has both analgesic and

CNS stimulant activity. Elevated norpethidine concentrations may increase the

risk of CNS effects (e.g., seizures), see section 4.3.

Alprazolam

1, single dose

200 q12h, 2 days

↑ 2.5 fold

500 q12h, 10 days

↓ 12%

↓ 16%

Alprazolam metabolism was inhibited following the introduction of ritonavir.

After ritonavir use for 10 days, no inhibitory effect of ritonavir was observed.

Caution is warranted during the first several days when alprazolam is co-

administered with ritonavir dosed as an antiretroviral agent or as a

pharmacokinetic enhancer, before induction of alprazolam metabolism develops.

Buspirone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A and as a result is expected to increase the plasma concentrations

of buspirone. Careful monitoring of therapeutic and adverse effects is

recommended when buspirone concomitantly administered with ritonavir.

Sleeping agent

Zolpidem

200, 4 doses

↑ 28%

↑ 22%

Zolpidem and ritonavir may be co-administered with careful monitoring for

excessive sedative effects.

Smoke cessation

Bupropion

100 q12h

↓ 22%

↓ 21%

600 q12h

↓ 66%

↓ 62%

Bupropion is primarily metabolised by CYP2B6. Concurrent administration of

bupropion with repeated doses of ritonavir is expected to decrease bupropion

levels. These effects are thought to represent induction of bupropion metabolism.

However, because ritonavir has also been shown to inhibit CYP2B6 in vitro, the

recommended dose of bupropion should not be exceeded. In contrast to long-

term administration of ritonavir, there was no significant interaction with

bupropion after short-term administration of low doses of ritonavir (200 mg

twice daily for 2 days), suggesting reductions in bupropion concentrations may

have onset several days after initiation of ritonavir co-administration.

Steroids

Inhaled, injectable or

intranasal fluticasone

propionate, budesonide,

triamcinolone

Systemic corticosteroid effects including Cushing's syndrome and adrenal

suppression (plasma cortisol levels were noted to be decreased 86% in the above

study) have been reported in patients receiving ritonavir and inhaled or intranasal

fluticasone propionate; similar effects could also occur with other corticosteroids

metabolised by CYP3A e.g., budesonide and triamcinolone. Consequently,

concomitant administration of ritonavir dosed as an antiretroviral agent or as a

pharmacokinetic enhancer and these glucocorticoids is not recommended unless

the potential benefit of treatment outweighs the risk of systemic corticosteroid

effects (see section 4.4). A dose reduction of the glucocorticoid should be

considered with close monitoring of local and systemic effects or a switch to a

glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclomethasone).

Moreover, in case of withdrawal of glucocorticoids progressive dose reduction

may be required over a longer period.

Dexamethasone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent

inhibits CYP3A and as a result is expected to increase the plasma concentrations

of dexamethasone. Careful monitoring of therapeutic and adverse effects is

recommended when dexamethasone is concomitantly administered with

ritonavir.

Prednisolone

200 q12h

↑ 28%

↑ 9%

Careful monitoring of therapeutic and adverse effects is recommended when

prednisolone is concomitantly administered with ritonavir. The AUC of the

metabolite prednisolone increased by 37 and 28% after 4 and 14 days ritonavir,

respectively.

ND: Not determined

1. Based on a parallel group comparison

2. Sulfamethoxazole was co-administered with trimethoprim.

Cardiac and neurologic events have been reported when ritonavir has been co-administered with

disopyramide, mexiletine or nefazodone. The possibility of medicinal product interaction cannot be

excluded.

In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of

increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal

products should be considered.

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding medicinal product interactions when ritonavir is used a pharmacokinetic

enhancer is also contained in the Summary of Product Characteristics of the co-administered protease

inhibitor.

Proton pump inhibitors and H

2

-receptor antagonists

Proton pump inhibitors and H

-receptor antagonists (e.g. omeprazole or ranitidine) may reduce

concentrations for co-administered protease inhibitors. For specific information regarding the impact of

co-administration of acid reducing agents, refer to the Summary of Product Characteristics of the co-

administered protease inhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors

(lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not

significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure

(about 6 - 18%).

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of

these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where

ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a

pharmacokinetic enhancer for other PIs. These data indicate no increase in the rate of birth defects

compared to rates observed in population-based birth defect surveillance systems. Animal data have

shown reproductive toxicity (see section 5.3). Norvir can be used during pregnancy if clinically needed.

Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe

method of contraception should be used during treatment.

Breastfeeding

Limited published data reports that ritonavir is present in human milk.

There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on

milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2)

developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed infant,

HIV infected women should not breast feed their infants under any circumstances if they are receiving

Norvir.

Fertility

No human data on the effect of ritonavir on fertility are available. Animal studies do not indicate harmful

effects of ritonavir on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Dizziness is a

known undesirable effect that should be taken into account when driving or using machinery.

4.8 Undesirable effects

Summary of the safety profile

Ritonavir dosed as a pharmacokinetic enhancer

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the

specific co-administered PI. For information on adverse reactions refer to the SPC of the specific co-

administered PI.

Ritonavir dosed as an antiretroviral agent

Adverse reactions from clinical trials and post-marketing experience in adult patients

The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in

combination with other antiretroviral drugs were gastrointestinal (including diarrhoea, nausea, vomiting,

abdominal pain (upper and lower)), neurological disturbances (including paraesthesia and oral

paraesthesia) and fatigue/asthenia.

Tabulated list of adverse reactions

The following adverse reactions of moderate to severe intensity with possible or probable relationship to

ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in order

of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to

< 1/100); rare (> 1/10,000 to < 1/1,000): not known (cannot be estimated from the available data).

Events noted as having a frequency not known were identified via post-marketing surveillance

Adverse reactions in clinical studies and post-marketing in adult patients

System Order Class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common

Decreased white blood cells, decreased

haemoglobin, decreased neutrophils, increased

eosinophils, thrombocytopenia

Uncommon

Increased neutrophils

Immune system disorders

Common

Hypersensitivity, including urticaria and face

oedema.

Rare

Anaphylaxis

Metabolism and nutrition disorders

Common

Hypercholesterolaemia, hypertriglyceridaemia,

gout, oedema and peripheral oedema,

dehydration (usually associated with

gastrointestinal symptoms)

Uncommon

Diabetes mellitus

Rare

Hyperglycaemia

Nervous system disorders

Very common

Dysgeusia, oral and peripheral paraesthesia,

headache, dizziness, peripheral neuropathy

Common

Insomnia, anxiety, confusion, disturbance in

attention, syncope, seizure

Eye disorders

Common

Blurred vision

Cardiac disorders

Uncommon

Myocardial infarction

Vascular disorders

Common

Hypertension, hypotension including

orthostatic hypotension, peripheral coldness

Respiratory, thoracic and mediastinal

disorders

Very common

Pharyngitis, oropharyngeal pain, cough

Gastrointestinal disorders

Very common

Abdominal pain (upper and lower), nausea,

diarrhoea (including severe with electrolyte

imbalance), vomiting, dyspepsia

Common

Anorexia, , flatulence, mouth ulcer,

gastrointestinal haemorrhage, gastroesophageal

reflux disease, pancreatitis

Hepatobiliary disorders

Common

Hepatitis (including increased AST, ALT,

GGT), blood bilirubin increased (including

jaundice)

Skin and subcutaneous tissue disorders

Very common

Pruritus, rash (including erythematous and

maculopapular)

Common

Acne

Rare

Stevens Johnson syndrome, toxic epidermal

necrolysis (TEN)

Musculosketal and connective tissue

disorders

Very common

Arthralgia and back pain

Common

Myositis, rhabdomyolysis, myalgia,

myopathy/CPK increased

Renal and urinary disorders

Common

Increased urination, renal impairment (e.g.

oliguria, elevated creatinine)

Uncommon

Acute renal failure

Reproductive system and breast

disorders

Common

Menorrhagia

General disorders and administration

site conditions

Very common

Fatigue including asthenia, flushing, feeling hot

Common

Fever, weight loss

Investigations

Common

Increased amylase, decreased free and total

thyroxine

Uncommon

Increased glucose, increased magnesium,

increased alkaline phosphatase

Description of selected adverse reactions

Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and

jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretrovirals.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination

antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic

infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however,

the reported time to onset is more variable and can occur many months after initiation of treatment (see

section 4.4).

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed

hypertriglyceridaemia. In some cases fatalities have been observed. Patients with advanced HIV disease

may be at risk of elevated triglycerides and pancreatitis (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk

factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The

frequency of this is unknown (see section 4.4).

Paediatric populations

The safety profile of Norvir in children 2 years of age and older is similar to that seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple

App Store.

4.9 Overdose

Symptoms

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir

1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case

of renal failure with eosinophilia has been reported.

The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea

and tremors.

Management

There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should

consist of general supportive measures including monitoring of vital signs and observation of the clinical

status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is

proposed that management of overdose could entail gastric lavage and administration of activated

charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is

unlikely to be beneficial in significant removal of the medicine.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: antiviral for systemic use, protease inhibitors ATC code: J05AE03

Ritonavir dosed as a pharmacokinetic enhancer

Pharmacokinetic enhancement by ritonavir is based on ritonavir's activity as a potent inhibitor of CYP3A-

mediated metabolism. The degree of enhancement is related to the metabolic pathway of the co-

administered protease inhibitor and the impact of the co-administered protease inhibitor on the

metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor is

generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on the

co-administered protease inhibitor. For additional information on the effect of ritonavir on co-

administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product

Characteristics of the particular co-administered PIs.

Ritonavir dosed as an antiretroviral agent

Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.

Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor

which leads to the production of HIV particles with immature morphology that are unable to initiate new

rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity

against human aspartyl proteases.

Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study

with clinical endpoints. However, due to ritonavir's metabolic inhibitory properties its use as a

pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical practice

(see section 4.2).

Effects on the Electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily)

controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The

maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400

mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that

observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of

≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500

msec.

Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study on

Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour

interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was

observed (see section 4.4).

Resistance

Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with

therapeutic doses of ritonavir.

Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations

V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20,

33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations associated

with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-

resistance. The Summary of Product Characteristics of other protease inhibitors or official continuous

updates should be consulted for specific information regarding protease mutations associated with

reduced response to these agents.

Clinical pharmacodynamic data

The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of

disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving HIV-1

infected patients. The following studies are the most important.

Adult Use

A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients

extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed a

reduction in mortality and AIDS defining events. The mean average change from baseline over 16 weeks

for HIV RNA levels was -0.79 log

(maximum mean decrease: 1.29 log

) in the ritonavir group versus-

0.01 log

in the control group. The most frequently used nucleosides in this study were zidovudine,

stavudine, didanosine and zalcitabine.

In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl)

without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced viral

load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks for HIV

RNA levels was -0.88 log

in the ritonavir group versus -0.66 log

in the ritonavir + zidovudine group

versus -0.42 log

in the zidovudine group.

The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of the

emergence of resistance as described under section 4.1.

Paediatric Use

In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant

difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, zidovudine and

lamivudine) following 48 weeks treatment.

In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4

weeks to 2 years received ritonavir 350 or 450 mg/m

every 12 hours co-administered with zidovudine

160 mg/m

every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat analyses, 72% and

36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at Week 16 and 104,

respectively. Response was similar in both dosing regimens and across patient age.

In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were protease

inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m

every 12

hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and 57% of

patients in the 350 and 450 mg/m

dose groups, respectively, achieved reduction in plasma HIV-1 RNA

to ≤ 400 copies/ml at Week 48.

5.2 Pharmacokinetic properties

Absorption

There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute

bioavailability has not been determined. The pharmacokinetics of ritonavir during multiple dose regimens

were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, ritonavir accumulation

is slightly less than predicted from a single dose due to a time and dose-related increase in apparent

clearance (Cl/F). Trough concentrations of ritonavir decrease over time, possibly due to enzyme

induction, but appeared to stabilise by the end of 2 weeks. The time to maximum concentration (T

remained constant at approximately 4 hours with increasing dose. Renal clearance averaged less than 0.1

l/h and was relatively constant throughout the dosage range.

The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown in

the table below.

Ritonavir Dosing Regimen

100 mg once

daily

100 mg twice

daily

200 mg once

daily

200 mg twice

daily

600 mg twice

daily

(µg/ml)

0.84 ± 0.39

0.89

3.4 ± 1.3

4.5 ± 1.3

11.2 ± 3.6

trough

(µg/ml)

0.08 ± 0.04

0.22

0.16 ± 0.10

0.6 ± 0.2

3.7 ± 2.6

12 or 24

(µgh/ml)

6.6 ± 2.4

20.0 ± 5.6

21.92 ± 6.48

77.5 ± 31.5

~3 to 5

Cl/F (L/h)

17.2 ± 6.6

16.1

10.8 ± 3.1

10.0 ± 3.2

8.8 ± 3.2

Values expressed as geometric means. Note: ritonavir was dosed after a meal for all listed regimens.

Ritonavir AUC and C

after administration of a single 100 mg dose powder for oral suspension are

bioequivalent to the 100 mg oral solution under fed conditions.

Effects of food on oral absorption

Administration of a single 100 mg dose of ritonavir powder for oral suspension with a moderate fat meal

(617 kcal, 29% calories from fat) was associated with a mean decrease of 23 and 39% in ritonavir AUC

and C

respectively, relative to fasting conditions. Administration with a high fat meal (917 kcal, 60%

calories from fat) was associated with a mean decrease of 32 and 49% in ritonavir AUC

and C

respectively, relative to fasting conditions.

Distribution

The apparent volume of distribution (V

/F) of ritonavir is approximately 20 - 40 l after a single 600 mg

dose. The protein binding of ritonavir in human plasma is approximately 98 - 99% and is constant over

the concentration range of 1.0 – 100 μg/ml. Ritonavir binds to both human alpha 1-acid glycoprotein

(AAG) and human serum albumin (HSA) with comparable affinities.

Tissue distribution studies with

C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys

and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of approximately 1

measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues. Ritonavir

penetrates minimally into the brain.

Metabolism

Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by

the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in

vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative

metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation

metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent compound.

However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent compound.

Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors

(and other products metabolised by CYP3A4) and other protease inhibitors may influence the

pharmacokinetics of ritonavir (see section 4.5).

Elimination

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily

via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is

expected to be unabsorbed ritonavir. In these studies renal elimination was not found to be a major route

of elimination of ritonavir. This was consistent with the observations in animal studies.

Special populations

No clinically significant differences in AUC or C

were noted between males and females. Ritonavir

pharmacokinetic parameters were not statistically significantly associated with body weight or lean body

mass. Ritonavir plasma exposures in patients 50 – 70 years of age when dosed 100 mg in combination

with lopinavir or at higher doses in the absence of other protease inhibitors is similar to that observed in

younger adults.

Patients with impaired liver function

After multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to

moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir after

dose normalisation was not significantly different between the two groups.

Patients with impaired renal function

Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment. However,

since the renal clearance of ritonavir is negligible, no changes in the total body clearance are expected in

patients with renal impairment.

Paediatric patients

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 years

of age receiving doses ranging from 250 mg/m

twice daily to 400 mg/m

twice daily. Ritonavir

concentrations obtained after 350 to 400 mg/m

twice daily in paediatric patients were comparable to

those obtained in adults receiving 600 mg (approximately 330 mg/m

) twice daily. Across dose groups,

ritonavir oral clearance (CL/F/m

) was approximately 1.5 to 1.7 times faster in paediatric patients above 2

years of age than in adult subjects.

Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 2

years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations in this

study were highly variable and somewhat lower than those obtained in adults receiving 600 mg

(approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m

) declined

with age with median values of 9.0 L/h/m

in children less than 3 months of age, 7.8 L/h/m

in children

between 3 and 6 months of age and 4.4 L/h/m

in children between 6 and 24 months of age.

5.3 Preclinical safety data

Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid gland

and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were

accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE) and

retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not

been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to

phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular

changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical

investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal

changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are

felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal

abnormalities were noted in clinical trials.

Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification

delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic

dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal

weights) occurred at a maternally toxic dosage.

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays

including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse

lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human

lymphocytes.

Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific

for these species, but are regarded as of no relevance for humans.

6. Pharmaceutical particulars

6.1 List of excipients

Copovidone

Sorbitan laurate

Silica, colloidal anhydrous

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

Following mixing with food or liquid as described in section 4.2: consume within 2 hours.

6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

Polyethylene/aluminium/polyethylene terephthalate foil sachet. 30 sachets per carton. Packaged with a

mixing cup and two 10 ml calibrated oral dosing syringes.

6.6 Special precautions for disposal and other handling

For details on preparation and administration of Norvir powder for oral suspension, refer the patient or

care giver to the Package Leaflet, section 3.

Administering with food

The entire contents of each sachet is to be poured over a small amount of soft food (e.g. apple sauce or

vanilla pudding). All of the mixed soft food must be administered within 2 hours.

Administering with liquid

The entire contents of each sachet should be suspended in 9.4 ml of liquid (water, chocolate milk, or

infant formula) giving a final concentration of 10 mg per ml. The patient/caregiver is to be instructed to

follow the directions below:

The oral dosing syringe and mixing cup should be dry prior to use.

Draw up 9.4 ml of liquid using the provided oral dosing syringe, remove the bubbles, and transfer the

liquid to the mixing cup. All measuring should be done in ml using the syringe.

Pour the entire contents of 1 sachet (100 mg) into the mixing cup.

Close the lid and shake hard for at least 90 seconds until all the lumps have dissolved.

Let the liquid stand for 10 minutes in order for most of the bubbles to disappear.

Use the provided oral dosing syringe to measure and administer the prescribed ml volume (see section

4.2). Be sure to remove the bubbles prior to dose administration.

Once the powder is mixed, the prepared suspension should be used within 2 hours.

Discard any mixture remaining in the mixing cup.

The oral dosing syringe and mixing cup should be cleaned immediately with warm water and dish soap

after use.

If the syringe breaks or becomes hard to use, the syringe should be thrown away and the new one used.

7. Marketing authorisation holder

AbbVie Deutschland GmbH & Co. KG

Knollstrasse

67061 Ludwigshafen

Germany

8. Marketing authorisation number(s)

EU/1/96/016/009

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 26 August 1996

Date of latest renewal: 26 August 2006

10. Date of revision of the text

24 May 2018

Detailed information on this product is available on the website of the European Medicines Agency

http://www.ema.europa.eu

Company Contact Details

AbbVie Limited

Address

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, SL6 4UB, UK

Telephone

+44 (0)1628 561 092

Out of Hours Telephone

+44 (0)1628 561 092

http://www.abbvie.co.uk

Medical Information e-mail

[email

protected]

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