Consumer medicine information

Invirase

Saquinavir mesilate

BRAND INFORMATION

Brand name

Invirase

Active ingredient

Saquinavir mesilate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Invirase.

What is in this leaflet

This leaflet answers some common questions about Invirase tablets. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Invirase against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

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

What Invirase is used for

Invirase belongs to a group of medicines called anti-HIV drugs. Within this group, Invirase belongs to a class of drugs called HIV protease inhibitors. Invirase is used for the treatment of HIV (Human Immunodeficiency Virus). It works by interfering with the viral reproductive cycle.

Invirase must be used only in combination with ritonavir (Norvir®) and other medicines to treat the HIV virus.

Please note that you should always report any changes in your condition to your doctor to ensure that any infections which occur due to your low immunity (called opportunistic infections) are treated promptly.

Your doctor may have prescribed Invirase for another purpose.

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

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

Invirase is not a cure for HIV infection and you may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.

Invirase does not reduce the risk of transmitting HIV to others through sexual contact or contamination through blood.

Before you take Invirase

When you must not take it

Do not take Invirase if:

  1. you have allergies to saquinavir or any ingredients listed at the end of this leaflet
  2. you have severe liver disease
  3. if you were born with or have:
  • any condition with abnormal electrocardiograms (ECG-electrical recording of the heart)
  • a salt imbalance in the blood, especially low concentrations of potassium (hypokalaemia) which are currently not corrected by treatment
  • a very slow heart rate
  • a weak heart (heart failure)
  1. you are taking medicines that can cause abnormal ECG changes
    These medicines include:
  • certain heart medicines such as amiodarone, bepridil, disopyramide, dofetilide flecainide, hydroquinidine, systemic lignocaine, propafenone, and quinidine
  • trazadone, a medicine to treat depression
  • clarithromycin, erythromycin and halofantrine, which are used to treat infections
  • astemizole, mizolastine and terfenadine which are medicines used to treat allergic conditions (antihistamines)
  • cisapride, a medicine used to treat stomach reflux
  • chlorpromazine, clozapine, haloperidol, pimozide, quetiapine, sertindole, thioridazine and ziprasidone which are medicines used to treat psychoses
  • trazodone; a medicine used as an antidepressant
  • atazanavir, another HIV protease inhibitor
  • tacrolimus, a medicine used to suppress your own immune system
  • quinine, a medicine use to treat night cramps and malaria
  • dapsone, a medicine used to treat leprosy
  1. you are taking certain other medicines
    Such medicines as:
  • dihydroergotamine, ergonovine ergotamine and methylergonovine which are used to treat migraine headaches
  • oral midazolam and triazolam which are used to help you sleep at night or for sedation before surgery
  • lovastatin and simvastatin which are used to lower cholesterol levels in the blood
  • rifampicin, an antibiotic used to prevent or treat certain types of bacterial infections such as tuberculosis
  • alfuzosin; a medicine used as a muscle relaxant to help with urination
  1. the package is torn or shows signs of tampering
  2. the expiry date (EXP) printed on the pack has passed
    If you take it after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking Invirase, talk to your doctor or pharmacist.

Invirase is not usually given to children less than 16 years of age.

Before you start to take it

Your doctor must know all about the following before you start to take Invirase.

  1. if you are pregnant or plan to become pregnant
    It is not known whether Invirase is harmful to an unborn baby when taken by a pregnant woman. If there is a need to take Invirase when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.
  2. if you are breastfeeding or plan to breastfeed
    It is not known whether Invirase passes into breast milk. Your doctor will decide whether or not you should breastfeed.
  3. if you are allergic to any other medicines, foods, dyes or preservatives
  4. If you have a history of:
  • arrhythmias or irregular heart rhythms
  • a very slow heart rate (bradycardia)
  • a weak heart (heart failure)
  • a disease of the heart muscle
    Invirase can change your heart's ECG (a test to check your heart rhythm ie electrocardiogram). This is more common if you are female or elderly.
    If you experience palpitations or any changes in your heart rate during treatment, you should tell your doctor immediately. Your doctor may wish to perform an ECG to measure your heart rhythm.
  1. if you have hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder)
    Invirase tablets contain lactose.
  2. if you have any other health problems including:
  • liver disease
  • kidney disease
  • haemophilia (a condition where patients have a tendency to bruise and bleed easily)
  • diabetes or high blood sugar levels
  • high cholesterol levels and high triglyceride levels, a blood fat
  • diarrhoea

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

Taking other medicines

Tell your doctor or pharmacist if you are taking ANY other medicines including any that you have bought without a prescription from a pharmacy, supermarket or health food shop.

There are some medicines that CANNOT BE TAKEN with Invirase (see "Before you take Invirase" above).

Other medicines may interfere with Invirase and your doctor may need to adjust the dose and / or monitor you more closely if you continue to take them. These include:

  • medicines used to treat fungal infections such as fluconazole, itraconazole, ketoconazole and miconazole
  • medicines used to treat epilepsy such as carbamazepine, phenobarbitone and phenytoin
  • medicines used to treat heart conditions called calcium channel blockers such as amlodipine, diltiazem, felodipine isradipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil
  • certain heart or blood pressure medicines
  • medicine to help you sleep at night or sedate you before surgery such as intravenous midazolam
  • antibiotics such as fusidic acid, pentamidine, quinupristin/dalfopristin, rifabutin and sparfloxacin
  • medicines used to treat diseases related to the acid in the stomach such as esomeprazole lansoprazole omeprazole, pantoprazole, rabeprazole and ranitidine
  • St John's wort (hypericum perforatum) which is a herbal product
  • garlic capsules
  • grapefruit juice
  • medicines used to treat HIV infection such as delavirdine didanosine, tenofovir disoproxil fumarate, efavirenz, enfuvirtide, fosamprenavir, indinavir, lopinavir, maraviroc nelfinavir, nevirapine, tenofovir disoproxil, tipranavir, zalcitabine and/or zidovudine
  • medicines used to treat erectile dysfunction such as sildenafil, tadalafil and vardenafil
  • medicines used to suppress the immune system such as cyclosporin and rapamycin
  • colchicine; a gout medication
  • warfarin; a medicine to prevent blood clots
  • medicines used to treat heart-related conditions such as digoxin, ibutilide, sotalol and vincamine i.v.
  • strong pain killers usually used in anaesthesia such as alfentanil and fentanyl
  • medicines used to treat anxiety such as alprazolam, clorazepate, diazepam and flurazepam
  • medicines used to treat depression such as nefazodone, tricyclic or tetracyclic antidepressants such as clomipramine or maprotiline
  • ethinyloestradiol based oral contraceptives
  • medicines to treat asthma and hay fever such as budesonide, dexamethasone, fluticasone and salmeterol.
  • bosentan; a medicines used to treat pulmonary arterial hypertension
  • medicines used to lower cholesterol such as atorvastatin, cerivastatin, fluvastatin and pravastatin
  • methadone; a medicine used to treat opioid dependence

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

Your doctor or pharmacist has a complete list of medicines to be careful with or avoid while taking Invirase.

If you have not told your doctor or pharmacist about any of the above, or any other medicines you are taking, tell them before you start taking Invirase.

How to take Invirase

How much to take

Take Invirase only when prescribed by your doctor. Your doctor will tell you how many Invirase film-coated tablets to take each day.

Invirase should only be taken only in combination with ritonavir (Norvir®), a medicine used to treat HIV.

The recommended is two 500 mg film-coated tablets of Invirase two times a day (a total of four Invirase tablets per day), with one 100 mg capsule of ritonavir (Norvir®) two times a day (a total of two Norvir® capsules).

If you have not received treatment before, the recommended starting dose of Invirase is one 500 mg film-coated tablet twice a day (total of two Invirase tablets a day) with one 100 mg capsule of ritonavir (Norvir®) two times a day (a total of two Norvir® capsules) for the first 7 days of treatment. After 7 days the recommended dose of Invirase is two 500 mg film-coated tablets of Invirase two times a day (a total of four Invirase tablets per day), with one 100 mg capsule of ritonavir (Norvir®) two times a day (a total of two Norvir® capsules).

If you are switching from another treatment the recommended dose is two 500 mg film-coated tablets of Invirase two times a day (a total of four Invirase tablets per day), with one 100 mg capsule of ritonavir (Norvir®) two times a day (a total of two Norvir® capsules).

Both medicines should be taken at the same time.

How to take it

Tablets should be swallowed whole with a glass of water.

When to take it

Take Invirase tablets within two hours after a meal to ensure maximum absorption and effectiveness.

Taking Invirase with a meal that is high in calories, fat and protein increases your body's ability to absorb the medicine and in turn increases its effectiveness.

Taking your medicine at the same time each day will have the best effect on the HIV infection. It will also help you remember to take the medicine.

How long to take Invirase

Invirase helps control your HIV infection but does not cure it. Therefore, continue taking Invirase for as long as your doctor prescribes.

If you forget to take Invirase

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember together with some food and then go back to taking it as you would normally.

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

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

In case of an overdose

If you think that you or anyone else may have taken too much Invirase, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

Keep telephone numbers for these places handy.

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

You may need urgent medical attention.

While you are taking Invirase

Things you must do

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

Do not take any other medicines whether they require a prescription or not without first telling your doctor.

Continue to use safe sexual practices while taking Invirase. Invirase has not been shown to decrease the chance of giving HIV to your partner.

If you are using an oestrogen-based oral contraceptive, you should also use an additional type of contraception.

If you become pregnant while taking Invirase, tell your doctor.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel that Invirase is not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may want to take regular blood samples to measure your blood glucose levels or liver enzymes.

Things you must not do

Do not stop taking Invirase or change the dose without your doctor's advice. Do not let yourself run out of medicine over the weekend or on holidays.

Do not give Invirase to anyone else even if their symptoms seem similar to yours.

Things to be careful of

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

Invirase generally does not cause problems with your ability to drive a car or operate machinery. However, Invirase may cause dizziness in some people. Make sure you know how you react to Invirase before you drive a car or operate machinery.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Invirase.

Invirase helps most people with HIV infection but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

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

  • diarrhoea
  • constipation
  • stomach discomfort/pain, distention, wind
  • vomiting or feeling sick
  • dizziness, headache
  • tiredness, weakness
  • generally feeling unwell
  • skin problems such as itching and rash
  • hair loss
  • dry mouth/lips
  • heartburn, indigestion or belching after eating
  • tingling, numbness, weakness of the arms or legs
  • inability to sleep or increased need for sleep
  • increased or decreased appetite
  • taste disturbance or loss of taste
  • decreased libido (sex drive)
  • shortness of breath, difficulty breathing, chest tightness or rapid deep breathing
  • muscle spasms, fits or seizures
  • allergic reaction- shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin
  • being short of breath when exercising
  • looking pale
  • yellowing of skin or eyes
  • increased bruising or bleeding

These are the more common side effects of Invirase. For the most part these have been mild.

There are some side effects that may occur with HIV the protease inhibitor class of drug. As mentioned above, Invirase belongs to this class of drugs, and may cause the following side effects:

  • diabetes (excessive thirst, increased appetite with weight loss, feeling tired, drowsy, weak, depressed, irritable and generally unwell, and passing large amounts of urine)
  • body fat distribution changes including loss of fat from the limbs and increased fat around the stomach, breast enlargement could also occur in women
  • metabolic abnormalities such as hypertriglyceridemia (increased blood levels of triglycerides); insulin resistance (diminished effectiveness of insulin in lowering the levels of blood sugar); hypercholesterolemia (increased blood levels of cholesterol); and hyperlactatemia (increased levels of lactic acid in the blood)
  • Within the first few weeks of treatment with anti-HIV medicines, some people, may experience a worsening of an infection that is being treated or experience new infections or may develop inflammatory reactions (e.g., pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV. If you become concerned about any new symptoms, or any changes in your health, please discuss with your doctor immediate

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking Invirase

Storage

Keep your Invirase tablets in the bottle until it is time to take them. If you take them out of the bottle they may not keep well.

Keep Invirase in a cool dry place where the temperature stays below 30°C. Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Invirase where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

Product Description

What Invirase looks like

Invirase 500 mg tablets are light orange to brownish orange in colour and oval in shape. The tablets are marked "SQV 500" on one side and "Roche" on the other side. They come in a white plastic bottle.

Ingredients

Active ingredient - saquinavir

  • each tablet contains 500 mg saquinavir as saquinavir mesilate.

Inactive ingredients

  • lactose monohydrate
  • microcrystalline cellulose (460)
  • croscarmellose sodium
  • povidone
  • magnesium stearate (470)
  • hypromellose
  • purified talc (553)
  • water
  • triacetin
  • colouring agents: iron oxide red (172), iron oxide yellow (172) and titanium dioxide (171).

Invirase tablets are gluten free.

Invirase 500 mg tablets come in packs of 120 tablets.

Manufacturer

Invirase is distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Number:

  • Invirase 500 mg tablets AUST R 119419.

This leaflet was prepared on 6 September 2018

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Invirase

Active ingredient

Saquinavir mesilate

Schedule

S4

 

1 Name of Medicine

Saquinavir mesilate.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

149845-06-7.

2 Qualitative and Quantitative Composition

Invirase film-coated tablets contain 571.5 mg of saquinavir mesilate equivalent to 500 mg saquinavir free base.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1.

Note.

Saquinavir soft gel capsules (Fortovase) are no longer marketed in Australia.

3 Pharmaceutical Form

Invirase 500 mg film-coated tablets are light orange to brownish orange, oval, cylindrical and biconvex. The tablets are marked “SQV 500” on one side and “ROCHE” on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiviral agent, ATC code: J05A E01.
The chemical name for saquinavir mesilate is cis-N-tert-Butyl-decahydro-2[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)- L-asparginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxyamide methanesulfonate. The molecular formula is C38H50N6O5.CH4O3S. Saquinavir mesilate has a molecular weight of 766.96.
Saquinavir mesilate is a white to off-white, fine powder with an aqueous solubility of 220 mg/100 mL at 25°C.

Mechanism of action.

Invirase is a highly selective inhibitor of the Human Immunodeficiency Virus enzyme, HIV proteinase (HIV protease).
The HIV protease is an essential viral enzyme required for the specific cleavage of viral gag and gag-pol polyproteins. These viral polyproteins contain a type of cleavage site, which is only recognised by HIV and closely related viral proteases. Saquinavir has been designed as a peptide-like structural mimetic of the viral cleavage site. Saquinavir is a selective and reversible inhibitor of the HIV protease that prevents the creation of mature infectious virus particles.

Pharmacodynamic effect.

Antiviral activity in vitro.

Saquinavir demonstrates antiviral activity against both laboratory strains and clinical isolates of HIV-1; with typical EC50 and EC90 values in the range 1-10 nanoM and 5-50 nanoM, respectively, using acutely infected T cell lines or primary human lymphocytes/ monocytes. In vitro antiviral activity was observed against a panel of HIV-1 group M nonclade B isolates (A, AE, C, D, F, G and H) and HIV-2 with EC50 values ranging from 0.3-2.4 nanoM. In the presence of 50% human serum or alpha-1 acid glycoprotein (1 mg/mL), the antiviral activity of saquinavir decreases by an average factor of 25-fold and 14-fold, respectively.

Resistance.

In vitro resistance.

In vitro selection of resistance from wild-type HIV-1 virus.

The most commonly reported mutations, G48V and L90M, were observed to develop during in vitro passage of HIV-1 wild-type virus in the presence of increasing concentrations of saquinavir. Recombinant virus harbouring the G48V and L90M mutations exhibited 7.9-fold and 3.4-fold reductions in viral susceptibility to saquinavir, respectively. Protease mutations such as M36I, I54V, K57R, and L63V developed less frequently in the presence of saquinavir.

In vivo resistance.

Treatment naïve patients.

Four studies have investigated boosted saquinavir regimens in ART naïve patients [saquinavir/ ritonavir (1600 mg/100 mg) daily, n = 349; (1000 mg/100 mg) twice daily, n = 92]. Baseline resistance analyses were conducted on 26 patients experiencing virological rebound. Data from 2 patients was excluded either because PI mutations were present at baseline or a signature protease mutation (D30N) associated with another PI subsequently developed. Virus from 2 patients (2/24) developed protease mutations (M36I and M46i/m, respectively). These mutations are not typically associated with saquinavir resistance. No specific saquinavir associated protease mutations were observed to develop following virological failure.

Treatment experienced patients.

Baseline and on-therapy genotype was evaluated for 22 previously PI experienced patients who experienced virological failure after receiving a boosted saquinavir regimen (MaxCmin 1 and 2 studies; 1000/100 mg twice daily, n = 171). Virus from 8 patients (8/22; 36%) developed additional protease mutations following virological failure. The relative incidence of each mutation was: I84V (n = 4, 18%); F53L, A71V or G73S (n = 2, 9%); L10V, M46I, I54V, V82A or L90M (n = 1, 4.5%).

Antiviral activity according to baseline genotype and phenotype.

Genotypic and phenotypic clinical cutoffs predicting the clinical efficacy of boosted saquinavir have been derived from retrospective analyses of 2 open label randomised clinical studies (RESIST 1 and 2) and a large independent hospital cohort study.
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was shown to be a predictive factor of virological outcome. Virological response was first observed to decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the fold shift exceeded 12-fold.
A clinical hospital cohort study (Marcelin et al., 2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to saquinavir/ ritonavir (1000/100 mg) twice daily in 138 saquinavir naïve patients. The presence of 3 or more mutations was associated with reduced response to saquinavir/ ritonavir.
To confirm the association between the number of these saquinavir associated resistance mutations and virological response using an independent dataset, the association was investigated using data for patients receiving boosted saquinavir in the RESIST 1 and 2 clinical studies. The RESIST 1 and 2 studies enrolled a more heavily treatment experienced patient population, including 54% who had received prior saquinavir. This analysis confirmed the association between the number of saquinavir associated mutations (p = 0.0133, see Table 4). In addition, the G48V mutation, previously identified in vitro as a saquinavir signature mutation, was present at baseline in virus from three patients, none of whom responded to therapy.
Virological response to HAART relies upon the activity of the individual antiretroviral components. The association between the number of saquinavir mutations at baseline and the activity of the concomitant antiretroviral components of the regimen was assessed using baseline phenotypic susceptibility data. The association between the number of baseline saquinavir resistance associated mutations and response was highly significant when the activity of the optimised background was taken into account (p = 0.0011, see Table 5). Patients receiving saquinavir in the presence of active concomitant ART and having fewer saquinavir associated mutations had an improved response compared to patients receiving fewer active comedication and higher numbers of saquinavir associated mutations.

Hypersusceptibility to mutant virus.

Hypersusceptibility of some resistant viruses to inhibition with saquinavir has been described, for example in the presence of the 30N substitution (with or without additional substitutions at residues 46, 71 or 88). This was also observed in complexes of substitutions showing resistance to amprenavir including 50V in presence or absence of 46I and 47V. A high proportion of viruses with substitutions at residue 82 either retain susceptibility (37%) or show enhanced activity (8%) to saquinavir. The clinical significance of hypersusceptibility to saquinavir has not been established.

Clinical trials.

Advanced patients without prior zidovudine therapy.

A dose ranging study (Italy, V13330) conducted in 92 zidovudine naïve patients (mean baseline CD4 = 179) studied saquinavir at doses of 75 mg, 200 mg and 600 mg tds in combination with zidovudine 200 mg tds compared to saquinavir 600 mg tds alone and zidovudine alone.
In analyses of average CD4 changes over 16 weeks, treatment with the combination of saquinavir 600 mg tds + zidovudine (n = 14) produced greater CD4 cell increases than zidovudine monotherapy (see Figure 1). The CD4 changes of zidovudine in combination with doses of saquinavir lower than 600 mg tds were no greater than that of zidovudine alone. The number of patients studied was too limited to permit adequate comparison of the efficacies of saquinavir 1800 mg daily versus recommended doses of zidovudine as monotherapy.

Advanced patients with prior zidovudine therapy.

In ACTG229/NV14255, 295 patients (mean baseline CD4 = 165) with a history of prolonged zidovudine treatment (median 713 days) were randomised to receive either saquinavir 600 mg tds + zalcitabine + zidovudine (triple combination), saquinavir 600 mg tds + zidovudine or zalcitabine + zidovudine. In analyses of average CD4 changes over 24 weeks, the triple combination (n = 89) produced greater increases in CD4 cell counts (see Figure 2) compared with that of zalcitabine + zidovudine. There were no significant differences in CD4 changes among patients receiving saquinavir + zidovudine and zalcitabine + zidovudine. Based on surrogate markers, including CD4 count and plasma HIV-RNA response but not quality of life measures, the combination of saquinavir 1800 mg daily with zidovudine and zalcitabine was superior to saquinavir + zidovudine and zidovudine + zalcitabine but longer term follow-up information including morbidity and mortality information are lacking.
Only limited and transient antiviral activity has been demonstrated with Invirase monotherapy. Therefore, Invirase must be given in combination with other antiretrovirals.

Saquinavir in combination with ritonavir.

MaxCmin1 study.

In the MaxCmin1 study, the safety and efficacy of saquinavir soft gel capsules (Fortovase)/ ritonavir (1000/100 mg) bd in combination with 2 NRTIs/NNRTIs was compared with indinavir/ ritonavir (800/100 mg) bd in combination with 2 NRTIs/ NNRTIs. Median baseline CD4 cell count was 272 cells/mm3 and median baseline plasma HIV-RNA was 4.0 log10 copies/mL in the Fortovase/ ritonavir arm. Median baseline CD4 cell count was 280 cells/mm3 and median baseline plasma HIV-RNA was 3.9 log10 copies/mL in the indinavir/ ritonavir arm. At 48 weeks, the median increases in CD4 cell counts were 85 and 73 cells/mm3 for the Fortovase and indinavir arms, respectively. For the intent to treat (ITT) analysis at week 48 (switch = failure) the proportion of patients in the saquinavir containing arm with viral load below the limit of detection (< 400 copies/mL) was 69% (n = 102) compared with 53% in the indinavir containing arm.

MaxCmin2 study.

In the MaxCmin2 study, the safety and efficacy of saquinavir soft gel capsules (Fortovase)/ ritonavir (1000/100 mg) bd in combination with 2 NRTIs/NNRTIs was compared with lopinavir/ ritonavir (400/100 mg) bd in combination with 2 NRTIs/NNRTIs in over 324 subjects. Values for median baseline CD4 count and median baseline plasma HIV RNA were 241 cells/mm3 and 4.4 log10 copies/mL in the Fortovase/ ritonavir arm, and 239 cells/mm3 and 4.6 log10 copies/mL in the lopinavir/ ritonavir arm, respectively.
In the primary efficacy analysis, incidence of virological failure, including all subjects that took at least one dose of the study medication (ITT/ exposed population) 29 failures were observed in the lopinavir/ ritonavir arm and 53 failures in the Fortovase/ ritonavir arm (hazard ratio HR: 0.5; 95% CI: 0.3-0.8). The better outcome in the lopinavir/ ritonavir arm was associated with lower failure rates among subjects no longer taking their assigned treatment and better compliance with the protocols intention to use ART strategies aimed at suppressing viral replication at all times. Comparable findings were made in the analysis where discontinuation of the assigned treatment was regarded as virological failure (ITT/ exposed population/ discontinuation = failure; HR: 0.6; 95% CI: 0.4-0.9). In this analysis the better outcome in the lopinavir/ ritonavir arm was associated with a reduced risk of discontinuation of the assigned treatment due to factors not linked to antiviral activity.
At 48 weeks, the proportion of subjects with HIV RNA below the limit of detection (< 50 copies/mL) was 53% (n = 161) for the Fortovase arm versus 60% (n = 163) for the lopinavir arm in the ITT, switch equals failure analysis, and 74% (n = 114) for the Fortovase arm versus 70% (n = 141) for the lopinavir arm in the on-treatment analysis (p = ns for both comparisons). At the cut off level of HIV RNA < 400 copies/mL, the probability of viral suppression was lower in the Fortovase/ ritonavir arm from week 24 and onwards in the ITT/ exposed population analysis and from week 36 in the ITT/ exposed population/ discontinuation analysis. No statistical differences were observed in the on-treatment analysis.
Over 48 weeks a similar strong immunological response was seen in both arms with median increases in CD4 count of 106 cells/mm3 for the lopinavir/ ritonavir arm, and 110 cells/mm3 for the Fortovase/ ritonavir arm.
More subjects in the Fortovase/ ritonavir arm (30%) than in the lopinavir/ ritonavir arm (14%) prematurely discontinued the assigned treatment (p = 0.001). The primary reasons for premature discontinuation were nonfatal adverse events and subject's choice.
No difference in the incidence of adverse events of grade 3 and/or 4 was seen between the two arms.

Effects on electrocardiogram.

The effect of 1000/100 mg bd (therapeutic dose) and 1500/100 mg bd (supratherapeutic dose) of Invirase/ ritonavir on the QT interval was evaluated over 20 hours on day 3 of dosing in a 4-way crossover, double blind, placebo and active controlled (moxifloxacin 400 mg) study in healthy male and female volunteers aged 18 to 55 years old (n = 59). The day 3 time point was chosen since the pharmacokinetic exposure was maximum on that day in a previous 14 day multiple dose pharmacokinetic study. These doses of Invirase/ ritonavir on day 3 in this study resulted in a mean Cmax of approximately 3-fold and 4-fold, respectively, higher than the mean Cmax observed with Invirase/ ritonavir 1000/100 mg bd in HIV patient population at steady state. On day 3, the upper 1-sided 95% CI of the maximum mean difference in predose baseline corrected QTcS (study specific heart rate corrected QT) between the active drug and placebo arms was > 10 msec for the two Invirase/ ritonavir treatment groups (see results in Table 6). The supratherapeutic dose of Invirase/ ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of Invirase/ ritonavir. Majority (89% and 80% in therapeutic dose and supratherapeutic dose, respectively) of subjects had the QTcS of < 450 msec and none had the QTc interval of > 500 msec. (See Section 4.4).
In this study, PR interval prolongation of > 200 msec was also observed in 40% and 47% of subjects receiving Invirase/ ritonavir 1000/100 mg bd and 1500/100 mg bd, respectively, on day 3. Three percent of subjects in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of > 200 msec. The maximum mean PR interval changes relative to the predose baseline value were 25 msec and 34 msec in the two Invirase/ ritonavir treatment groups, 1000/100 mg bd and 1500/100 mg bd, respectively. (See Section 4.4).
There was no torsades de pointes and no QT prolongation > 500 msec in the study. In several subjects, association of syncope or presyncope with PR prolongation could not be ruled out. The clinical significance of these findings from this study in healthy volunteers to the use of Invirase/ ritonavir in HIV infected patients is unclear, but doses exceeding Invirase/ ritonavir 1000/100 mg bd should be avoided.
The effect of treatment initiation with a dosing regimen of Invirase/ ritonavir 500/100 mg bd in combination with 2 NRTIs for the first 7 days of treatment followed by Invirase/ ritonavir 1000/100 mg bd in combination with 2 NRTIs in the subsequent 7 days on QTc interval, PK, and viral load was evaluated in an open label 2 week observational study in 23 HIV-1 infected, treatment naïve patients initiating Invirase/ ritonavir therapy. ECG and PK measurements were collected on days 3, 4, 7, 10, and 14 of treatment with the modified Invirase/ ritonavir treatment. The primary study variable was maximal change from dense predose baseline in QTcF (ΔQTcFdense). The modified Invirase/ ritonavir regimen reduced mean maximum ΔQTcFdense in the first week of treatment compared with the same value in healthy volunteers receiving the standard Invirase/ ritonavir dosing regimen in the TQT study on day 3 (see Table 7), based on cross study comparison in a different population. Only 2/21 (9%) patients across all study days had maximum QTcF change from dense predose baseline ≥ 30 msec following administration of the modified Invirase/ ritonavir regimen in the treatment naïve HIV-1 infected patient population; and the maximum mean change from dense predose baseline in QTcF was < 10 msec across all study days. These results suggest that the QTc liability is reduced with the modified Invirase/ ritonavir dosing regimen, based on a cross study comparison in a different population (see Table 7). The proportion of patients with a reported PR interval prolongation > 200 msec in this study ranged from 3/22 (14%) (day 3) to 8/21 (38%) (day 14).
Following the modified Invirase/ ritonavir regimen, SQV exposure during the first week peaked on day 3 and declined to the lowest exposure on day 7 with RTV induction effects, while day 14 SQV PK parameters (following full doses of Invirase/ ritonavir in the second week) approached the range of historical mean values for SQV steady-state values in HIV-1 infected patients (see Table 7). Mean Invirase Cmax with the modified Invirase/ ritonavir regimen was approximately 53-83% lower across study days in the HIV-1 infected patients relative to the mean Cmax achieved in healthy volunteers in the TQT study on day 3. Continuous declines in HIV-RNA were observed in all treatment naïve patients receiving the modified Invirase/ ritonavir dosing regimen over the 2 week treatment period, suggesting HIV viral suppression during the time of the study. No long-term efficacy was evaluated with the modified regimen.

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability of saquinavir 200 mg capsules is very low: following administration of a 600 mg oral dose to healthy volunteers, in the presence of food, the mean absolute bioavailability was 4% (range: 1%-9%). The low bioavailability is thought to be due to a combination of incomplete absorption (approximately 30%) and extensive first-pass metabolism. Gastric pH has been shown not to play a major role in the large increase in bioavailability when given with food.
In healthy volunteers the extent of absorption (as reflected by AUC) after a 600 mg oral dose of saquinavir given 30 minutes before food to fasted subjects, was substantially increased when the same dose was given following a full breakfast (including eggs, bacon, cereal, toast, coffee or tea) from 110 nanogram.h/mL to 390 nanogram.h/mL. The presence of food also increased the time taken to achieve maximum concentration from 1.7 hours to 2.5 hours and substantially increased the mean maximum plasma concentrations (Cmax) from 41 nanogram/mL to 173 nanogram/mL. This effect of food has been shown to be present for up to 2 hours after food intake (systemic exposure (AUC) was similar for doses given 5 minutes and 2 hours after a standardised meal). Therefore, Invirase should be taken within 2 hours after a meal.
In another study in healthy volunteers, it was shown that the increased extent of absorption of a 600 mg oral dose of saquinavir following a full breakfast was approximately double the absorption after a light breakfast (only cereal, toast, coffee or tea).
In a crossover study, 22 HIV infected patients treated with Invirase/ ritonavir (1000/100 mg) twice daily and receiving 3 consecutive doses under fasting conditions or after a high fat meal (46 g fat, 1091 kcal), the AUC0-12 of saquinavir was 10,320 nanogram.h/mL and 34,926 nanogram.h/mL, respectively. All but 1 of the patients achieved Ctrough above the therapeutic threshold in the fasted state. Nevertheless, Invirase should be administered within 2 hours following a meal.
In HIV infected patients, boosted saquinavir (Fortovase (soft gel capsules) or Invirase) at doses of 400/400 mg twice daily or 1000/100 mg twice daily provides saquinavir systemic exposures over a 24 hour period similar to, or greater than those achieved with Fortovase 1200 mg three time daily (see Table 8).
In treatment naïve HIV-1 infected patients initiating Invirase/ ritonavir treatment with a modified Invirase/ ritonavir dosing regimen of Invirase 500 mg bd with ritonavir 100 mg bd for the first 7 days of treatment and increased to Invirase 1000 mg bd with ritonavir 100 mg bd in the subsequent 7 days, Invirase systemic exposures generally approached or exceeded the range of historical steady-state values with the standard Invirase/ ritonavir 1000 mg/100 mg bd dosing regimen across study days (see Tables 8 and 9).
No differences in gastrointestinal absorption were noted between HIV positive subjects with and without diarrhoea, and administration of saquinavir had no effect on these parameters.
Saquinavir is a substrate for the MDR1 Multidrug Transporter (P-gp).
Bioequivalence of Invirase 500 mg film coated tablets and Invirase 200 mg capsules was demonstrated in 94 healthy male and female volunteers who received 1000 mg (either as two 500 mg tablets or five 200 mg capsules) under fed conditions in combination with 100 mg ritonavir twice daily. Mean exposure ratios were estimated to be 1.10 for AUC0-∞ and 1.19 for Cmax of saquinavir with corresponding 90% CI of 1.04-1.16 and 1.14-1.25, respectively.

Distribution.

Saquinavir partitions extensively into the tissues. The mean steady-state volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 L. Saquinavir shows a high degree of protein binding (approximately 98%) which is independent of concentrations over the range 15-700 nanog/mL. Saquinavir does not enter the cerebrospinal fluid readily and concentrations are low compared with plasma, as would be expected from saquinavir's high protein binding.

Metabolism.

Saquinavir is metabolised extensively via the hepatic route. Values > 96% of a radiolabelled intravenous dose appeared in the faeces after 4 days. In vitro studies identified that the metabolism of saquinavir is cytochrome P450 mediated, with the specific isoenzyme CYP3A4 responsible for more than 90% of the hepatic metabolism. Renal excretion is a very minor route of elimination for saquinavir (< 4%). The metabolic profile of saquinavir has been investigated in bile, plasma and microsomes in rats and in microsomes from other species, including man. Saquinavir is rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds.

Excretion.

Systemic clearance is rapid, 80 L/hr; which is close to hepatic plasma flow. Systemic clearance was constant after intravenous doses of 6, 36 and 72 mg infused over 3 hours. The mean residence time of saquinavir was found to be 7 hours.
After single and multiple oral doses of capsules (25-600 mg tds) in the presence of food, the increase in exposure (50-fold) was greater than directly proportional to the increase in dose (24-fold). Accumulation following multiple dosing (25-600 mg tds) in HIV infected patients is modest. AUC was increased by 150% at steady state compared to single doses.

Pharmacokinetics in special populations.

Patients with renal impairment.

No pharmacokinetic investigations of Invirase in patients with renal insufficiency have been performed.

Patients with hepatic impairment.

The effect of hepatic impairment on the steady-state pharmacokinetics of Invirase/ ritonavir (1000/100 mg) for 14 days, was investigated in 7 HIV infected patients with moderate liver impairment (Child-Pugh grade B score 7-9). The study included a control group consisting of 7 HIV infected patients with normal hepatic function matched with the hepatically impaired patients for age, gender, weight and tobacco use. The mean (% coefficient of variation in parentheses) values for saquinavir AUC0-12 and Cmax were 24.3 (102%) microgram.hr/mL and 3.6 (83%) microgram/mL, respectively, for HIV infected patients with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) microgram.hr/mL and 4.3 (68%) microgram/mL. The geometric mean ratio (ratio of pharmacokinetic parameters in hepatically impaired patients to patients with normal liver function) (90% CI) was 0.7 (0.3-1.6) for both AUC0-12 and Cmax, which suggests approximately 30% reduction in the pharmacokinetic exposure in patients with moderate hepatic impairment. No dose adjustment is warranted for saquinavir in HIV infected patients with moderate hepatic impairment (see Section 4.4).

Effect of gender, race and age.

Gender.

No effect of gender was observed on the pharmacokinetics of Invirase 200 mg capsule administered as a 600 mg single dose in 71 healthy volunteers. A gender difference was observed with females showing higher saquinavir exposure than males (AUC 56%, Cmax 26%) in the bioequivalence study comparing Invirase 500 mg film coated tablets with Invirase 200 mg capsules (boosted therapies). There was no evidence that age and bodyweight explained the gender difference in this study. A clinically significant difference in safety profile and efficacy between men and women has not been reported with the approved dosage regimen. Treatment with Invirase/ ritonavir (1000/100 mg) twice dialy in male and female patients is found to be well tolerated and effective.

Race.

The influence of race on the pharmacokinetics of Invirase has not been determined.

Elderly.

Invirase pharmacokinetics have not been investigated in elderly patients (> 65 years).

Paediatric.

Invirase pharmacokinetics have not been investigated in paediatric patients (< 12 years) (see Section 4.4).

5.3 Preclinical Safety Data

Genotoxicity.

Saquinavir, with and without metabolic activation as appropriate, was not mutagenic in the Salmonella typhimurium reverse mutation assay or in the chinese hamster lung V79/HPRT test, was not clastogenic in the mouse micronucleus assay in vivo or in human peripheral blood leucocytes in vitro, and did not induce DNA damage in primary rat hepatocytes.

Carcinogenicity.

Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir 125-1000 mg/kg/d and 200-2500 mg/kg/d, respectively, for approximately 2 years. The plasma exposures (area under the curve [AUC] values) in the respective species were up to approximately 37% and 85% of those obtained in humans at the recommended clinical dose of Invirase/ ritonavir (1000/100 mg) twice daily.

4 Clinical Particulars

4.1 Therapeutic Indications

Invirase (saquinavir) is indicated for the treatment of HIV/AIDS in adults. Saquinavir must be used only in combination with ritonavir and other antiretroviral therapies (see Section 5.1).
This indication is based on changes in surrogate markers. At present there are no results from controlled clinical trials evaluating the effect of regimens containing saquinavir on HIV disease progression or survival (see Section 5.1).

4.3 Contraindications

Please also refer to the full product information for ritonavir which is used in combination with Invirase.
Invirase is contraindicated in patients with:
hypersensitivity to saquinavir or to any of the excipients in the film coated tablet (see Section 6.1);
severe hepatic impairment (see Section 4.4);
congenital or documented acquired QT prolongation, and electrolyte disturbances particularly uncorrected hypokalaemia. Familial history of sudden death at a young age may be suggestive of congenital QT prolongation.
Invirase is contraindicated with other medicines that may interact and result in potentially life threatening side effects associated with concomitantly administered medicines. Examples of medicines which are contraindicated with Invirase are included in Table 1.

4.4 Special Warnings and Precautions for Use

Information for patients.

Invirase must be given only in combination with ritonavir (see Section 4.2). Please refer to the ritonavir full prescribing information for additional precautionary measures. Invirase is not recommended for use in combination with any other pharmacoenhancer (e.g. cobicistat), as dosing recommendations have not been established.
Invirase should not be given without ritonavir.
Invirase may interact with other medicines, therefore, patients should consult their doctor before taking other medications (prescription or nonprescription).
Alternative or additional contraceptive measures should be used when oestrogen based oral contraceptives are coadministered (see Section 4.5).
Patients should also be advised that they may experience toxicities associated with coadministered medications.
Patients should be informed that Invirase is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.
Patients should be advised that Invirase does not reduce the risk of transmitting HIV to others through sexual contact or contamination through blood.
Patients should have regular visits with their doctor for blood tests and monitoring of blood glucose concentrations.

Use in hepatic impairment.

Invirase is contraindicated in patients with severe hepatic impairment (see Section 4.3).
No dosage adjustment is necessary for HIV infected patients with moderate hepatic impairment based on limited data (see Section 4.2; Section 5.2). In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease and development of portal hypertension while on treatment with Invirase. Associated symptoms include jaundice, ascites, oedema and, in some cases oesophageal varices. Several of these patients died. A causal relationship between Invirase therapy and development of portal hypertension has not been established. Careful monitoring for signs and symptoms of liver toxicity, and tests of liver function (including transaminases) are recommended.

Use in renal impairment.

Clinical studies with saquinavir included patients with a range of renal impairment from mild to moderate (highest creatinine value measured: 143 micromol/L). In these patients, exposure to saquinavir was not correlated with laboratory markers of renal impairment. No data are available in patients with more severe renal impairment. Although renal clearance is only a minor elimination pathway for saquinavir, clinical judgment should be exercised when administering Invirase to patients with renal insufficiency.

Diabetes and hyperglycaemia.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycaemia have been reported during postmarketing surveillance in HIV infected patients receiving PI therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made.

Fat redistribution.

Redistribution and/or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump) and breast enlargement, ‘cushingoid appearance’ and loss of body fat from the face, limbs and upper trunk (peripheral lipodystrophy) have been reported in HIV positive patients receiving antiretroviral therapy (ART). It has also been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, and hyperglycaemia. The severity of these metabolic abnormalities differs within and between the three classes of antiretrovirals (PIs, NRTIs, and NNRTIs). A higher risk of lipodystrophy has been associated with older age, longer duration of ART, stavudine use, hypertriglyceridaemia and hyperlactaemia. Clinical examination should include evaluation for physical signs of fat redistribution. Measurement of serum lipids and blood glucose is recommended. In case of such metabolic abnormalities, a switch in ART may be considered, and/or the addition of treatments designed to directly correct these abnormalities (e.g. lipid lowering agents). The mechanisms of these events and long-term consequences, such as an increased risk of cardiovascular disease, are currently unknown.

Immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome has been reported in patients treated with combination antiretroviral therapy, including Invirase. During the initial phase of combination antiretroviral treatment in patients with severe immune deficiency, a systemic inflammatory reaction to asymptomatic or residual opportunistic pathogens or self-antigens may arise and cause serious clinical conditions or aggravation of symptoms, which may necessitate further evaluation and treatment.
Autoimmune disorders have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Patients with 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. A causal relationship has been suggested. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Patients with diarrhoea.

The effects of diarrhoea on the absorption and clinical efficacy of saquinavir have not been studied systematically. The possibility that severe or prolonged diarrhoea may impair the efficacy of Invirase should be kept in mind.

Cardiac conduction and repolarisation abnormalities.

Dose dependent prolongations of QT and PR intervals have been observed in healthy volunteers receiving Invirase/ ritonavir (see Section 4.3).
It is not recommended to administer Invirase/ ritonavir to patients concurrently with other medicinal products that prolong the QT interval. Caution is advised if concomitant use is considered necessary and an ECG performed if signs of cardiac arrhythmias occur. Invirase/ ritonavir should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, and ischemic heart disease or cardiomyopathies as they may be at increased risk for developing cardiac conduction abnormalities.
Invirase/ ritonavir should be discontinued if significant arrhythmias, QT or PR prolongations occur. Generally, women and elderly patients may be more susceptible to drug associated effects on the QT interval. The magnitude of QT and PR prolongation may increase with increasing concentrations of saquinavir. Therefore, the recommended dose of Invirase/ ritonavir should not be exceeded. Invirase at a dose of 2000 mg once daily with ritonavir 100 mg once daily has not been studied with regard to the risk of QT prolongation and is not recommended.

Patients initiating therapy with Invirase/ ritonavir.

An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not initiate treatment with Invirase/ ritonavir. For patients with a QT interval < 450 msec, an on-treatment ECG is recommended.
For treatment naïve patients initiating treatment with Invirase 500 mg twice daily and ritonavir 100 mg twice daily for the first 7 days of treatment followed by Invirase 1000 mg twice daily and ritonavir 100 mg twice daily is recommended. With a baseline QT interval < 450 msec, an on treatment ECG is suggested after approximately 10 days of therapy.
Patients with a QT interval increased to > 480 msec or prolongation over pretreatment by > 20 msec should discontinue Invirase/ ritonavir (see Section 5.1).

Patients stable on Invirase/ ritonavir and requiring concomitant medication with potential to increase the QT interval or patients on medication with potential to increase the QT interval and requiring concomitant Invirase/ ritonavir where no alternative therapy is available and the benefits outweigh the risks.

An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy (see Section 4.5). If baseline QT interval < 450 msec, an on-treatment ECGs should be performed. For patients demonstrating a subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either Invirase/ ritonavir or the concomitant therapy or both.

Lactose intolerance.

Each 500 mg film coated tablet contains 38.5 mg lactose (monohydrate). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption (autosomal recessive disorder) should not take Invirase.

Drug interactions.

Saquinavir could interact and modify the pharmacokinetics of other drugs that are substrates for CYP3A4 and/or P-glycoprotein (P-gp) and should be used with caution. The example of drugs which are known to or have potential to interact with saquinavir are listed below (see Section 4.5; Section 4.3).

Paediatric use.

The safety and efficacy of Invirase/ ritonavir in HIV infected patients younger than 2 years have not been established. No dose recommendation for children 2 to < 16 years of age could be established that are both reliably effective and below thresholds of concern for QT and PR interval prolongation.
Limited information is available in children. Unboosted Invirase should not be used in children due to the significantly lower saquinavir plasma levels in children compared with adults.

Use in the elderly.

Only limited experience is available in patients older than 60 years. No data are available to establish a dose recommendation in elderly patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Most medicine interaction studies with saquinavir have been completed without the administration of ritonavir (i.e. unboosted) with saquinavir soft gel capsules (Fortovase). Observations from medicine interaction studies conducted with unboosted saquinavir might not be representative of the effects seen with the boosted saquinavir therapy. Furthermore, results seen with Fortovase may not be predictive for Invirase and vice versa.
The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme, CYP3A4, responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-gp. Therefore, medicines that either share or modify CYP3A4 and/or P-gp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other medicines that are substrates for CYP3A4 or P-gp.

Drugs with additive effects on QT and PR interval prolongation.

Based on the finding of dose dependent prolongations of QT and PR intervals in healthy volunteers receiving Invirase/ ritonavir (see Section 4.3; Section 4.4; Section 5.1) additive effects on QT and PR interval prolongation may occur with the following medicinal classes: anti-arrhythmics class IA or class III, neuroleptics, tricyclic anti-depressive agents, phosphodiesterase type 5 (PDE5) inhibitors, certain antimicrobials and anti-histaminics and medicines which affect cardiac conduction (see Table 2). This effect might lead to an increased risk of ventricular arrhythmias, notably torsade de pointes. Therefore, concurrent administration of these agents with Invirase/ ritonavir should be avoided when alternative treatment options are available. Medicines showing both pharmacokinetic interactions with Invirase/ ritonavir and additive effects on QT and PR interval prolongation are strictly contraindicated. The combination of Invirase/ ritonavir with other medicines known to prolong the QT and PR interval is not recommended and should be used with caution if concomitant use is deemed necessary (see Section 4.3; Section 4.4).

Inhibitors of CYP3A4.

An increase in plasma concentrations of saquinavir could occur with other compounds that are inhibitors of the CYP3A4 isoenzyme. In a clinical study, ketoconazole (a potent CYP3A4 inhibitor) did not increase PK exposure of saquinavir when it was co-administered with ritonavir, suggesting that a second CYP3A4 inhibitor in a therapy may not further elevate the plasma levels of saquinavir. However, clinical monitoring of patients for saquinavir toxicity is recommended when Invirase is coadministered with CYP 3A4 inibitors (see Table 2, Examples of known and predicted drug-drug interactions).
Ritonavir can affect the pharmacokinetics of other medicines because it is a potent inhibitor of CYP3A4 and P-gp and is also an enzyme inducer of several cytochrome P450 isozymes (see Table 1: Medicines that are contraindicated with Invirase/ritonavir and the product information for ritonavir).

Inducers of CYP3A4 or P-gp.

Other medicines that induce CYP3A4 may also reduce saquinavir plasma concentrations.

Medicines reducing gastrointestinal transit time.

It is unknown whether medicines that reduce the gastrointestinal transit time could lead to lower saquinavir plasma concentrations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility and reproductive performance were not affected in rats at plasma exposures (AUC values) approximately 33% of those achieved in humans at the recommended clinical dose of Invirase/ ritonavir (1000/100 mg) twice daily.
(Category B1)
Reproduction studies conducted with saquinavir in rats and rabbits have shown no embryotoxicity or teratogenicity at plasma exposures (based on AUC) approximately 32% of those achieved in humans at the recommended clinical dose of Invirase/ ritonavir (1000/100 mg) twice daily. Only small amounts of saquinavir were shown to cross the placental barrier in these species. In a perinatal and postnatal study in rats, at plasma exposures similar to those in the teratogenicity study, there was no effect on the survival, growth and development of offspring to weaning.
Because animal reproduction studies are not always predictive of human response and clinical experience in pregnant women is limited, caution should be exercised before Invirase is prescribed during pregnancy.
It is not known whether saquinavir is excreted in animal or human milk. Because many medicines are excreted in human milk, and because of the potential for serious adverse reactions to saquinavir in nursing infants, breast feeding should be stopped during treatment with Invirase.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The most frequently reported adverse effects, with at least a possible relationship to boosted Invirase (i.e. adverse reactions) were nausea, diarrhoea, fatigue, vomiting, flatulence, and abdominal pain.

Adverse reactions from clinical trials with boosted saquinavir.

Limited data are available from 2 studies where the safety of saquinavir soft gel capsules (Fortovase) (1000 mg twice daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks was studied in 311 patients. Adverse reactions (including marked laboratory abnormalities) from these pivotal studies are summarised in Table 3.
Adverse effects from clinical trials with saquinavir soft gel capsules (Fortovase) are given for completeness, however, due to the higher bioavailability of Fortovase, these adverse effects might not be predictive of the safety profile of Invirase.
The following descriptors are used to describe the frequency of adverse reactions in Table 3; very common (≥ 10%), common (≥ 1% and < 10%). Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.
Additionally, for completeness, the following adverse reactions reported in clinical trials with unboosted saquinavir and not mentioned in Table 3 are listed below by body system.

General disorders and administration site conditions.

Chest pain, fever, intoxication, mucosal damage, oedema, pyrexia, retrosternal pain, shivering, wasting syndrome, weight decrease.

Cardiovascular disorders.

Cyanosis, heart murmur, heart valve disorder, hypertension, hypotension, syncope, thrombophlebitis, distended vein.

Endocrine/ metabolic disorders.

Appetite decrease, appetite disturbance, dehydration, hyperglycaemia, weight increase, xerophthalmia.

Gastrointestinal disorders.

Ascites, buccal mucosa ulceration, cheilitis, dysphagia, eructation, faeces bloodstained, faeces discoloured, gastralgia, gastritis, gastrointestinal inflammation, intestinal obstruction, gingivitis, glossitis, haemorrhage rectum, haemorrhoids, hepatomegaly, hepatosplenomegaly, melaena, pelvic pain, painful defecation, pancreatitis, parotid disorder, salivary gland disorders, stomatitis, tooth disorder, vomiting.

Hepatobiliary disorders.

Jaundice, portal hypertension, exacerbation of chronic liver disease with grade 4 elevated liver function test.

Investigations.

Blood creatinine phosphokinase increased, blood glucose increased, blood glucose decreased, raised transaminase values.

Blood and the lymphatic system.

Anaemia, haemolytic anaemia, microhaemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.

Musculoskeletal and connective tissue disorders.

Arthralgia, arthritis, back pain, muscle cramps, musculoskeletal disorders, musculoskeletal pain, myalgia, polyarthritis, stiffness, tissue changes, trauma.

Nervous system disorders.

Ataxia, frequent bowel movements, confusion, convulsions, coordination abnormal, dysarthria, dysesthesia, extremity numbness, heart rate disorder, hyperaesthesia, hyperreflexia, hypoaesthesia, hyporeflexia, intracranial haemorrhage, dry mouth, face numbness (facial pain), paresis, poliomyelitis, progressive multifocal leukoencephalopathy, seizures, spasms, tremor.

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

Skin papilloma, acute myeloid leukaemia.

Psychiatric disorders.

Agitation, amnesia, anxiety, confusional state, depression, excessive dreaming, euphoria, hallucination, insomnia, intellectual ability reduced, irritability, lethargy, libido disorder, overdose effect, psychic disorder, somnolence, speech disorder, suicide attempt.

Reproductive system.

Enlarged prostate, vaginal discharge.

Resistance mechanism.

Abscess, angina tonsillaris, candidiasis, herpes simplex, herpes zoster, staphylococcal infection, other bacterial infections, mycotic infections, influenza, lymphadenopathy, tumour.

Respiratory.

Bronchitis, cough, epistaxis, haemoptysis, laryngitis, pharyngitis, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection.

Skin and cutaneous tissue disorders.

Acne, dermatitis, dermatitis bullous skin eruption, drug eruption, seborrheic dermatitis, erythema, folliculitis, furunculosis, hair changes, hot flushes, photosensitivity reaction, skin pigment changes, maculopapular rash, severe cutaneous reaction associated with increased liver function tests, skin disorder, skin nodule, skin ulceration, Stevens-Johnson syndrome, increased sweating, urticaria, verruca, xeroderma.

Special senses.

Blepharitis, earache, ear pressure, eye irritation, dry eye syndrome, decreased hearing, otitis, taste alteration, tinnitus, visual disturbance.

Renal and urinary disorders.

Micturition disorder, urinary tract infection, nephrolithiasis.

Vascular disorders.

Vasoconstriction.

Postmarketing experience with saquinavir.

Serious and nonserious adverse effects from postmarketing spontaneous reports (where saquinavir was taken as the sole protease inhibitor or in combination with ritonavir), not mentioned in any section above, for which a causal relationship to saquinavir cannot be excluded, are listed below.

Nervous system disorders.

Somnolence; convulsions.

Immune system disorders.

Hypersensitivity.

Hepatobilary disorders.

Hepatitis.

Metabolism and nutrition disorders.

Diabetes mellitus or hyperglycaemia, sometimes associated with ketoacidosis;
metabolic abnormalities such as hypertriglyceridemia; hypercholesterolemia; insulin resistance; hyperlactatemia;
lipodystrophy (including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsicervical fat accumulation (buffalo hump)).

Vascular disorders.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dose.

Invirase must be given in combination with ritonavir (ritonavir boosted Invirase). Please also see the complete product information for ritonavir.
The recommended dose of Invirase is 1000 mg twice daily (2000 mg total daily dose) with ritonavir 100 mg twice daily in combination with other antiretroviral agents.
For treatment naïve patients initiating treatment with Invirase, the recommended starting dose of Invirase is 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment. After 7 days, the recommended dose of Invirase is 1000 mg twice daily with ritonavir 100 mg twice daily.
Patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from a non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen, except rilpivirine (see Section 4.3), without a washout period, should initiate and continue Invirase at the standard recommended dose of 1000 mg twice daily with ritonavir 100 mg twice daily.
Ritonavir should be taken at the same time as Invirase and within 2 hours after a meal. Note that food increases the bioavailability of Invirase and that in particular, a full meal has a greater effect than a light meal (see Section 5.2).
For the recommended dose and possible adverse effects of other antiretroviral agents used in combination therapy, please see the complete product information for these medicines. For patients already taking ritonavir as part of their antiretroviral regimen, no additional ritonavir is needed.
As with all antiretroviral therapies, adherence to the prescribed regimen is strongly recommended.

Special dosage instructions.

For serious toxicities that may be associated with Invirase, the treatment should be interrupted. Invirase should not be administered at less than the recommended dose (see Section 4.2). For combination treatment involving some other antiretrovirals dose modifications of the protease inhibitors may be required since plasma levels might increase (see Section 4.5).
For dosage instructions in special populations, please see Section 4.4.

4.7 Effects on Ability to Drive and Use Machines

No studies have been conducted on the ability to drive and to use machines whilst using Invirase. There is no evidence that Invirase may alter the patient's ability to drive and use machines, however, the adverse event profile of Invirase should be taken into account (see Section 4.8).

4.9 Overdose

There is limited experience of overdose with saquinavir.
Whereas acute or chronic overdose of saquinavir alone did not result in major complications, in combination with other protease inhibitors overdose symptoms and signs such as general weakness, fatigue, diarrhoea, nausea, vomiting, hair loss, dry mouth, hyponatraemia, weight loss and orthostatic hypotension, have been observed.
There is no specific antidote for overdose with saquinavir. Treatment should consist of general supportive measures including monitoring of vital signs and ECG, and observations of the patient's clinical status. If indicated, prevention of further absorption can be considered. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, purified talc, iron oxide yellow CI77492, iron oxide red CI77491, triacetin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Invirase tablets should be stored below 30°C.

6.5 Nature and Contents of Container

Invirase tablets are available in bottles of 120.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

Summary Table of Changes