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4.3    Contraindications

4.4    Special warnings and precautions for use

Atazanavir: Co-administration of atazanavir with ritonavir in at  doses greater than 100 mg once daily has not been clinically evaluated.  The use of higher ritonavir doses might 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 Reyataz Summary of Product Characteristics for further details.

4.5    Interaction with other medicinal products and other forms of interaction

4.2    Posology and method of administration

Adult use:

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily

Atazanavir 300 mg daily with ritonavir 100 mg daily

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily

Lopinavir 400 mg co‑formulated with ritonavir 100 mg twice daily

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily

Tipranvir 500 mg twice daily with ritonavir 200 mg twice daily

         Darunavir 600 mg twice daily with ritonavir 100 mg twice daily

4.4    Special warnings and precautions for use

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^nd or 3^rd degree atrioventricular block in patients with underlying structural heart disease and pre‑existing conduction system abnormalities or in patients receiving drugs 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).

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 Norvir 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 select medicinal products (eg 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 (eg digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral drugs” 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. 

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding drug 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 H₂-receptor antagonists: proton pump inhibitors and H₂-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 SmPC 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%).

4.8          Undesirable effects

5.1          Pharmacodynamic properties

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 ³ 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).

10.         Date of revision of the text

18 June 2008

4.4    Special warnings and precautions for use

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).

4.5          Interaction with other medicinal products and other forms of interaction

10.         Date of revision of the text

                 27 March 2008

4.5          Interaction with other medicinal products and other forms of interaction

Drugs 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 drug 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, stop St John’s wort 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 reduced affected by select co‑administered medicinal products (eg delavirdine, efavirenz, phenytoin and rifampicin).  These interactions are noted in the drug interaction tables below.

4.3          Contraindications

4.5          Interaction with other medicinal products and other forms of interaction

4.2    Posology and method of administration

Special Populations:  Ritonavir pharmacokinetics have not been evaluated in elderly patients. Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2).

5.2          Pharmacokinetic properties

Special Populations:  No clinically significant differences in AUC or C_max 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. Ritonavir pharmacokinetics have not been evaluated in elderly patients.

4.4    Special warnings and precautions for use

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 events.  Co‑administration of saquinavir and ritonavir has led to severe adverse events, 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).

4.5          Interaction with other medicinal products and other forms of interaction

4.6          Pregnancy and lactation

A limited number (> 800) of pregnant women were exposed to ritonavir during pregnancy; a very limited number (< 300) 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 limited 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 5.3).  The use of Norvir may be considered in pregnancy only when the benefits outweigh the risk to the foetus.

Ritonavir adversely interacts with oral contraceptives (OCs).  Therefore, an alternative, effective and safe method of contraception should be used during treatment.

No treatment‑related malformations were observed with ritonavir in either rats or rabbits.  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.  There are no studies in pregnant women.  This medicine should be used during pregnancy only if the potential benefits clearly outweigh the potential risks.

5.3          Preclinical safety data

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.

4.4    Special warnings and precautions for use

Osteonecrosis: Although the etiology 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.

4.8          Undesirable effects

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).

Text Layout changes for below sections:

Change to section 2 - Qualitative and quantitative composition,
Change to section 3 - Pharmaceutical form,

Change to section 4.1 - Therapeutic indications,

Change to section 4.2 - Posology and method of administration,

Change to section 4.3 - Contraindications,

Change to section 4.4 - Special warnings and precautions for Use,

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction,

Change to section 4.7 - Effects on Ability to Drive and Use Machines,

Change to section 4.8 - Undesirable Effects,
Change to section 5.2 - Pharmacokinetic Properties,

Change to section 6.1 - List of Excipients,

Change to section 6.2 - Incompatibilities,

Change to section 6. 4 - Special Precautions for Storage,

Change to section 6. 5 - Nature and Contents of Container,

Change to section 6. 6 - Instructions for use, handling and disposal,

Change to section 10 date of revision of the text
 

Text Layout changes for below sections:

Change to section 2 - Qualitative and quantitative composition,
Change to section 3 - Pharmaceutical form,

Change to section 4.1 - Therapeutic indications,

Change to section 4.2 - Posology and method of administration,

Change to section 4.3 - Contraindications,

Change to section 4.4 - Special warnings and precautions for Use,

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction,

Change to section 4.7 - Effects on Ability to Drive and Use Machines,

Change to section 6.1 - List of Excipients,

Change to section 6.2 - Incompatibilities,

Change to section 6. 4 - Special Precautions for Storage,

Change to section 6. 5 - Nature and Contents of Container,

Change to section 6. 6 - Instructions for use, handling and disposal,

Change to section 10 date of revision of the text
 

4.3         Contraindications

Alfuzosin

4.4    Special warnings and special precautions for use

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).

4.5              Interaction with other medicinal products and other forms of interaction

Saquinavir/rifampicin: 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 and ritonavir should not be given together with rifampicin.

Alfuzosin: based on results of a interaction study with ketoconazole, another potent inhibitor of CYP3A4, and alfuzosin, a significant increase in alfuzosin exposure is expected in the presence of ritonavir.  Therefore, alfuzosin should not be co-administered with ritonavir.

4.3         Contraindications

Alfuzosin

4.4    Special warnings and special precautions for use

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).

4.5              Interaction with other medicinal products and other forms of interaction

Saquinavir/rifampicin: 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 and ritonavir should not be given together with rifampicin.

Alfuzosin: based on results of a interaction study with ketoconazole, another potent inhibitor of CYP3A4, and alfuzosin, a significant increase in alfuzosin exposure is expected in the presence of ritonavir.  Therefore, alfuzosin should not be co-administered with ritonavir.

4.3         Contraindications

Alfuzosin

4.4    Special warnings and special precautions for use

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).

4.5              Interaction with other medicinal products and other forms of interaction

Saquinavir/rifampicin: 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 and ritonavir should not be given together with rifampicin.

Alfuzosin: based on results of a interaction study with ketoconazole, another potent inhibitor of CYP3A4, and alfuzosin, a significant increase in alfuzosin exposure is expected in the presence of ritonavir.  Therefore, alfuzosin should not be co-administered with ritonavir.