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Boehringer Ingelheim Limited

The Crescent Building, , Northwood, Santry, Dublin 9,
Telephone: +353 1 295 9620
Fax: : +353 1 816 3642
Medical Information e-mail: Medinfo@dbl.boehringer-ingelheim.com
Summary of Product Characteristics last updated on medicines.ie: 08/08/2017
SPC Aptivus 250 mg

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 08/08/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   27-Jul-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.5 minor editorial update

Section 4.8 update to Adverse Event Reporting details

Section 10 Date of Revision

Updated on 02/03/2016 and displayed until 08/08/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Feb-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.4

The following text deleted:


Diabetes mellitus/hyperglycaemia

New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

 

Lipid elevations

Treatment with Aptivus co-administered with low dose ritonavir and other antiretroviral agents has resulted in increased plasma total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating tipranavir therapy and during therapy. Treatment-related lipid elevations should be managed as clinically appropriate.

 

Fat redistribution

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors, has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with factors related to the active substance such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

and Replaced with:

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. A higher increase of blood lipids were seen with tipranavir/ritonavir than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Section 4.8

Facial wasting, lipohypertrophy, lypotrophy and lipodystrophy acquired deleted from adverse reaction list.

the following paragraph added:

Metabolic parameters

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

Metabolic parameters

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

the following paragraph deleted:

Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated with redistribution of body fat in some patients, including loss of peripheral subcutaneous fat, increased intra-abdominal fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance and hyperglycaemia.

Section 10

Date of revision of text amended to February 2016

Updated on 10/07/2015 and displayed until 02/03/2016
Reasons for adding or updating:
  • 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 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.4 - Special precautions for storage
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Jun-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



 

Section 2


Excipients with known effect
(per capsule): Each soft capsule contains

100.0 mg ethanol, 455.0 mg macrogolglycerol ricinoleate and 12.6 mg sorbitol (constituent in « Sorbitol Special-Glycerin Blend »)


Section 3

Pink, oblong soft gelatin Each capsules is pink and is imprinted with "TPV 250" in black.

Section 4.1
Second paragraph below deleted.

This indication is based on the results of two phase III studies, performed in highly pre-treated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus in mostly treatment-experienced adolescent patients aged 12 to 18 years (see section 5.1).

Section 4.2

Aptivus with ritonivir should not be used in treatment naive patients.

Posology

Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time.

Adults and adolescents (from 12-18 years of age)
The recommended dose of Aptivus is 500 mg, co-administered with 200 mg ritonavir (low does ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).
.....

Paediatric population

- Adolescents from 12 years of age:

The recommended dose of Aptivus is 500 mg, co-administered with 200 mg ritonavir (low dose ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).

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


.....

- Children under 12 years of age:

The safety and efficacy of Aptivus capsules in children aged 2 to 12 years has not been established.

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

Also, appropriate dose adjustments for children under 12 years cannot be achieved with Aptivus capsules. Aptivus oral solution is available for children between 2 and 12 years of age (please refer to the respective SmPC for further details).

The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data are available.

 

Missed dose

Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time.


Heading Older people amended to Elderly.

Patients with liver impairment amended to Liver Impairment.

Patients with renal impairment amended to Renal Impairment.

Paediatric population

The safety and efficacy of Aptivus capsules in children aged 2 to 12 years has not been established.

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

Also, appropriate dose adjustments for children under 12 years cannot be achieved with Aptivus capsules. Aptivus oral solution is available for children between 2 and 12 years of age (please refer to the respective SmPC for further details).

The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data are available.



Method of administration
Oral use.
.....

Section 4.3

Herbal preparations containing St John’s wort (Hypericum perforatum) must not be used while taking Aptivus due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, is contraindicated. These active substances include antiarrhythmics (such as amiodarone, bepridil, quinidine), antihistamines (such as astemizole, terfenadine), ergot derivatives (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (such as cisapride), antipsychotics (such as pimozide, sertindole, quetiapine), sedatives/hypnotics (such as orally administered midazolam and triazolam) and HMG-CoA reductase inhibitors (such as simvastatin and lovastatin) (see section 4.5). Also contraindicated is the use of the alpha-1 adrenoceptor antagonist alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. In addition, co-administration of Aptivus with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure is contraindicated (see section 4.5).

Co-administration of colchicine with Aptivus/ritonavir is contraindicated in patients with renal or hepatic impairment (see section 4.5).

Section 4.4
The following paragraph is deleted:

Older people: Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see section 5.2).

In general, caution should be exercised in the administration and monitoring of Aptivus in older people reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy (see section 4.2).

Paragraph headed Bleeding  the word “studied” is replaced with the word “monitored”.

 

Various Italicised paragraph headings have had the colon after the heading removed.

 

Section 4.5

Colon removed from end of paragraph heading, Cmax amended to Cmax  and Cmin amended to Cmin with “max” and “min” as subscript throughout the interactions table.

 

Section 4.6

 

Contraception in males and females

Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment (see section 4.5).

 

This text moved to beginning of the section instead of just before Breastfeeding.

 

Section 4.7

No studies on the effects on the ability to drive and use machines have been performed performed for Aptivus/ritonavir. However, dDizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

 

Section 4.8

In the opening paragraph adverse events amended to adverse reactions.

 

After the Tabulated summary of adverse reactions the following text is deleted:

 

* This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to Aptivus in randomised controlled clinical trials and compassionate use (n=6300).

 

And replaced with:

 

* see section Description of selected adverse reactions “Bleeding” for source of information.

 

Various italicised headings are no longer underlined, and colon deleted from after the headings.

 

In the paragraph headed Bleeding the following text is added:

 

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials (n=6300).

 

And the word “studied” is amended to “monitored

 

Section 4.9

 

In the first paragraph undesirable effects deleted and replaced with adverse reactions.

 

Section 5.1

 

The following text is added to the beginning of the section headed “Clinical pharmacodynamics data”:

 

This indication is based on the results of two phase III studies, performed in highly pre-treated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus in mostly treatment-experienced adolescent patients aged 12 to 18 years.

 

Various Italicised paragraph headings have had the colon after the heading removed.

 

Section 5.2

 

Various Italicised paragraph headings have had the colon after the heading removed.

 

Section 6.1

 

Underlined headings have had the colon removed from the end of the heading and the fullstop from the end of the list.

 

Section 6.4

 

Store in a refrigerator (2°C - 8°C)

 

Section 9

 

Date of last renewal amended to 19 June 2015

 

Section 10

 

Date of revision of the text amended to June 2015.

Updated on 12/09/2014 and displayed until 10/07/2015
Reasons for adding or updating:
  • 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 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Aug-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.3
The following paragraph was added at the end of section 4.3:

Co-administration of colchicine with Aptivus/ritonivir is contraindicated in patients with renal or hepatic impairment (see section 4.5).


Section 4.4

The paragraph "The administration of colchicine and Aptivus, co-administered with low-dose ritonivir, is not recommended (see section 4.5)." is replaced with "In patients with normal renal and hepatic function, a reduction in colchicine dosage or an interruption of colchicine treatment is recommended in co-administration (see section 4.5)."

Section 4.5

Changes to the interaction table, particularly inclusion of Emtricitabine, Etravirine, Rilpivirine, Cobicistat and cobicistat containing products, Boceprevir, and Telaprevir; amendment to Colchicine, Atorvastatin, Sildenafil and Vardenafil, and a minor change to Antacids.

Section 10

Date of revision amended. 

Updated on 25/07/2014 and displayed until 12/09/2014
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Jul-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.4 Special Warnings and Precautions for Use

Text regarding class labelling on the risk of sexual transmission has been added to this section as the third paragraph.

 

What was previously the third paragraph text of “Patients should be advised that there is still a risk of passing HIV to others through blood or sexual contact when taking Aptivus.  Appropriate precautions should continue to be employed” has been deleted from this section.

 

Section 4.8 Undesirable Effects

The AE reporting details at the end of the section have been updated to replace the IMB details with those of the HPRA.

 

Section 10 Date of Revision of the Text

The date has been updated to July 2014.

 

Updated on 31/03/2014 and displayed until 25/07/2014
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Feb-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.2
Minor change to replace Elderly patients with Older people.

Section 4.4
Minor change to replace Elderly patients with Older people.

Section 4.7
The following was added:
for Aptivus/ritonavir. However, dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery

Section 4.8
In adverse reactions table:
Under Gastrointestinal disorders Common loose stools deleted.
Under Musculoskeletal and connective tissue disorders cramp deleted and spasms added.
Under Renal and urinary disorders renal insufficiency changed to renal failure.

Adverse event reporting statements added.

Section 5.2
Minor change to replace elderly with older people.

Section 10
Date of revision amended.

Updated on 21/01/2014 and displayed until 31/03/2014
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   01-Dec-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.3
The words 'such as' included in front of drug names, neuroleptics replaced with antipsychotics, quetiapine added and 'for caution on parentally administered midaxolam deleted.

Section 4.5
Neuroleptics replaced with Antipsychotics, Quetiapine added and including coma added.
Updated on 23/12/2013 and displayed until 21/01/2014
Reasons for adding or updating:
  • Change to section 6.5 - Nature and contents of container
Date of revision of text on the SPC:   01-Dec-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

‘outer shell HDPE , inner shell polypropylene’, amended to ‘outer and inner shell polypropylene’
Updated on 10/06/2013 and displayed until 23/12/2013
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-May-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.4
(at end of Immune Reactivation Syndrome paragraph)
Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Section 4.8
(in section entitled Description of selected adverse reactions)
Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Section 10
Date of revision amended.
Updated on 05/04/2013 and displayed until 10/06/2013
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • 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 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Mar-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company


This update follows a recent variation to update the patient information leaflet to better align with the SPC and to bring into line with current templates in use.  The update also includes some minor administration changes to the SPC mainly with regard to formatting.
Updated on 18/01/2012 and displayed until 05/04/2013
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   19-Dec-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.8
Sections principally reformated into a tabular format, with some rewording to the text and also to change the frequency of intracranial haemorrhage from uncommon, to rare.

Section10
Date of revision of text amended to 19 December 2011.
Updated on 04/08/2011 and displayed until 18/01/2012
Reasons for adding or updating:
  • 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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 4.3 - Contraindications
Date of revision of text on the SPC:   29-Jun-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.3
Sentence added: "Also contraindicated is the use of the alpha-1 adrenoceptor antagonist alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension."

Section 4.4
Text deleted "current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact" and replaced with "there is still a risk of passing HIV to others through blood or sexual contact when taking APTIVUS".

Paragraphs also added on Colchicine, Salmeterol and Bosentan.

Section 4.5
Lines added regarding "Integrase strand transfer inhibitors", "Colchicine", "Bosentan", "Salmeterol", "Nucleoside analogue DNA polymerase inhibitors", "Alpha 1-adrenoreceptor antagonists".  Updated information in line for "Sildenafil/Vardenafil" and "Tadalafil".

Section 5.1
Paragraph added on ECG evaluation.

Section 10
Date of Revision amended.
Updated on 28/10/2010 and displayed until 04/08/2011
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   05-Oct-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.2

Title of Posology added above paragraph beginning "Patients should be advised of the need ....."
Addition of paragraph regarding dosing for Adults.
New sub-heading of Paediatric popution.
Children under 12 years of age - editorial changes.
Information regarding use in children under 2 - minor editorial changes.
Elderly - editorial changes.
Addition of Paragraph Method of Administration - regarding taking with food at end of this section.

Section 4.4

Elderly - "Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see section5.2)." added.
Sentence "Therfore tipranavir with ritonavir should not be used in treatment-naive patients."
Sentence about macrogolglycerol ricinoleate moved.
Sentence about Aptivus containing a small amount of alcohol moved.

Section 4.6

The word "Fertility" included in heading, sub-headings of Pregnancy, Contraception in males and females, breastfeeding and Fertility with new paragraph on fertility included.

Section 4.8

This SPC change is following renewal of the licence, this section has been re-ordered, with too many changes to list in detail here.

Section 4.9

Sentence added "Human experience with tipranavir overdose is very limited.  No specific signs and symptoms of overdose are known.  Generally, an increased frequency and higher severity of undesirable effects may result from overdose."

Section 5.1

"Antivirals for systemic use" added after Pharmacotherapeutic group.
Paediatric patients changed to Paediatric population.

Section 5.2

Sub-heading of metabolism amended to Biotransformation.
Sub-heading of Paediatrics amended to Paediatric population.

Section 9

Date of latest renewal added.

Section 10

Date of revision of text amended.
Updated on 12/01/2010 and displayed until 28/10/2010
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • 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 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Nov-2009
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Product

Aptivus 250mg soft capsules

Changed Section

Section 4.2 (Posology and method of administration)

Details of Change

The following text has been added:

Patients should be advised of the need to take APTIVUS and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of APTIVUS and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of APTIVUS and ritonavir at the regularly scheduled time.

 

Changed Section

Section 4.4 (Special Warnings and Precautions for Use)

Details of Change

Some minor rewording regarding the co-administration of APTIVUS with:

atorvastatin

omeprazole and other proton pump inhibitors.

 

Changed Section

Section 4.5 (Interactions with other medicinal products)

Details of Change

Complete rewrite into tabular format.

 

Changed Section

Section 10 (Date of revision of the text)

Details of Change

November 2009

Updated on 04/08/2009 and displayed until 12/01/2010
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • 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
Date of revision of text on the SPC:   30-Jun-2009
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Section 4.1

Now contains the following information:

APTIVUS, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated adults and adolescents 12 years of age or older with virus resistant to multiple protease inhibitors. APTIVUS should only be used as part of an active combination antiretroviral regimen in patients with no other therapeutic options.

This indication is based on the results of two phase III studies, performed in highly pre-treated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase II study investigating pharmacokinetics, safety and efficacy of APTIVUS in mostly treatment-experienced adolescent patients aged 12 to 18 years (see section 5.1).

Section 4.2

Now contains the following information:

Adults and adolescents from 12 years of age

The recommended dose of APTIVUS is 500 mg, co-administered with 200 mg ritonavir (low dose ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).

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

Since currently only limited efficacy and safety data are available for adolescents (see section 5.1) close monitoring of virologic response and tolerance is particularly warranted in this patient group.

Children under 12 years of age:

No data are available on the efficacy and safety of APTIVUS capsules in children under 12 years of age. Also, appropriate dose adjustments for children under 12 years cannot be achieved with APTIVUS capsules. APTIVUS oral solution is available for children between 2 and 12 years of age (please refer to the respective SPC for further details).

APTIVUS is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy.

Section 4.4

Now contains the following information:

Switching from APTIVUS capsules to the oral solution:

APTIVUS capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution. Also, the composition of the oral solution is different from that of the capsules, with the high vitamin E content being especially noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore patients should not be switched from APTIVUS capsules to APTIVUS oral solution (see sections 5.1 and 5.2).

Switching from APTIVUS oral solution to the capsules:

APTIVUS oral solution is not interchangeable with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the same dose as capsules. However, children previously treated with APTIVUS oral solution and becoming 12 years of age should be switched to capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule formulation of APTIVUS could be associated with decreased exposure. Therefore, it is recommended that patients switching from APTIVUS oral solution to capsules at the age of 12 years are closely monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).

Rash

 

In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.

Section 4.8

Now contains the following information:

Paediatrics

In an open-label, dose-finding study of APTIVUS plus ritonavir (Trial 1182.14), 28 children who were 12 years of age or above received APTIVUS capsules. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in pediatric patients aged 12 to 18 years who took Aptivus capsules (reported in 2 or more children, Trial 1182.14, week 48 analyses, Full Analysis Set).

Total patients treated (N)

28

Events [N(%)]

 

Vomiting/ retching

3 (10.7)

Nausea

2 (7.1)

Abdominal pain1

2 (7.1)

Rash2

3 (10.7)

Insomnia

2 (7.1)

ALAT increased

4 (14.3)

1. Includes abdominal pain (N=1) and dyspepsia (N=1).

2. Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruitic, and urticaria

Section 5.1

Now contains the following information:

Paediatric patients

HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose, compared to the 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non-protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500 mg/200 mg twice daily could change to APTIVUS capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic and immunologic responses through 48 weeks.

No data are available on the efficacy and safety of APTIVUS capsules in children less than 12 years of age. Since APTIVUS capsules and oral solution are not bioequivalent, results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2). In patients with a body surface area of less than 1.33 m2 appropriate dose adjustments cannot be achieved with the capsule formulation.

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients receiving APTIVUS capsules are displayed in the tables below. Data on the 29 patients who switched to capsules during the first 48 weeks are presented. Due to limitations in the study design (e.g. non-randomized switch allowed according to patient/clinician decision), any comparisons between patients taking capsules and oral solution are not meaningful.

 

Baseline characteristics for patients 12 – 18 years of age who took capsule

Variable

 

Value

Number of Patients

 

29

Age-Median (years)

 

15.1

Gender

 

% Male

 

48.3%

Race

 

% White

 

69.0%

% Black

 

31.0%

% Asian

 

0.0%

Baseline HIV-1 RNA

(log10 copies/mL)

Median

(Min – Max)

 

4.6 (3.0 – 6.8)

% with VL > 100,000 copies/mL

 

27.6%

Baseline CD4+ (cells/mm3)

Median

(Min – Max)

 

330 (12 – 593)

% 200

 

27.6%

Baseline % CD4+ cells

 

Median

(Min – Max)

 

18.5% (3.1% – 37.4%)

 

Previous ADI*

 

% with Category C

 

29.2%

Treatment history

 

% with any ARV

 

96.6%

 

Median # previous NRTIs

 

5

 

Median # previous NNRTIs

 

1

 

Median # previous PIs

 

3

* AIDS defining illness

Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule

Endpoint

Result

Number of patients

29

Primary efficacy endpoint:

% with VL < 400

31.0%

Median change from baseline

in log10 HIV-1 RNA (copies/mL)

-0.79

Median change from baseline

in CD4+ cell count (cells/mm3)

39

Median change from baseline

in % CD4+ cells

3%

 


Updated on 13/07/2009 and displayed until 04/08/2009
Reasons for adding or updating:
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   29-May-2009
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Details of Main Changes

Section 4.5 - Now includes a table with information on the interaction of Aptivus with buprenorphine/naloxone

Updated on 18/03/2009 and displayed until 13/07/2009
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   03/2009
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Changed Sections: Section 4.5 (Interaction with other medicinal products and other forms of interaction)
 
Details of Main Changes
Section 4.5: Addition of information on the interaction of Aptivus with Fusion Inhibitors.
Updated on 18/03/2009 and displayed until 18/03/2009
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Updated on 27/01/2009 and displayed until 18/03/2009
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   12/2008
Legal Category:   prescription only

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Section 4.5: Co-administration of Aptivus with low-dose ritonavir and buproprion may result in decreased buproprion Cmax and AUC0-12h.

Updated on 02/12/2008 and displayed until 27/01/2009
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   10/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.3 - Combination of rifampicin with Aptivus and low-dose ritonavir is contraindicated

Section 4.5 - Rifampicin causes profound decreases in concentrations of other protease inhibitors which can

result in virological failure and resistance development.

Updated on 26/08/2008 and displayed until 02/12/2008
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.3 - Preclinical safety data
Date of revision of text on the SPC:   07/2008
Legal Category:   prescription only

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Change to section 4.4 Special warnings and precautions for use

Change to section 5.3 Preclinical safety data

 

Main Change

Section 4.4 Special warnings and precautions for use:

Information on interactions with Vitamin E has been added.  It is not recommended to co-administer more than 1200 IU vitamin E per day.

 

Updated on 11/06/2008 and displayed until 26/08/2008
Reasons for adding or updating:
  • 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 4.8 - Undesirable effects
Date of revision of text on the SPC:   04/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

 

Section 4.4 Special warnings and precautions for use:

Aptivus co-administered with low dose ritonavir decreases the plasma concentrations of the proton pump inhibitors omeprazole and esomeprazole.

 

Section 4.5 Interaction with other medicinal products and other forms of interaction:

Further information on the interaction of aptivus and low-dose ritonavir with omeprazole is included.

Updated on 07/03/2008 and displayed until 11/06/2008
Reasons for adding or updating:
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   12/2007
Legal Category:   prescription only

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Section 5.3 has been updated to include information regarding in vitro inhibition of platelet binding and thromboxane A2 binding.

Updated on 13/12/2007 and displayed until 07/03/2008
Reasons for adding or updating:
  • 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 4.2 - Posology and method of administration
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   10/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

 

Section 4.2 (Posology and method of administration) contains new information regarding use in the elderly as follows: “Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently to younger subjects.”

 

Section 4.4 (special warnings and special precautions for use) includes a new sentence to note that Aptivus soft capsules contain a small amount of alcohol.

 

Section 4.5 (Interaction with other medicinal products and other forms of interaction) has been updated to include new data on efavirenz, nevirapine, taladafil. In summary; a drug interaction study with efavirenz showed no evidence of a clinically relevant interaction between the efavirenz and Aptivus co-administered with low dose ritonavir. Data from a phase IIa study suggests no significant interaction with nevirapine and it is now advised that no dose adjustments are necessary. A pharmacokinetic study showed Aptivus/ritonavir increased taladafil exposure at the first dose but did not increase taladafil exposure at steady state. It is recommended to prescribe taladafil after at least 7 days of Aptivus/ritonavir dosing.

 

Updated on 30/08/2007 and displayed until 13/12/2007
Reasons for adding or updating:
  • 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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   07/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Orally administered midazolam and metoprolol have been added to the list of CYP3A cleared drugs and CYP 2D6 cleared drugs, respectively. Co-administration of Aptivus with drugs which are highly dependent on these pathways for clearance is contra-indicated.

Section 4.4 has been updated with the following information regarding co-administration of anti-consultants: " Caution should be used when prescribing carbamazepine, Phenobarbital and phenytoin. Aptivus may be less effective due to decreased tipranavir plasma concentrations in patients taking these agents concomitantly.

Section 4.5 has been updated with the following information: "A cocktail study was conducted in 16 healthy volunteers with twice daily Aptivus/ritonavir 500/200 mg capsules administration for 10 days to assess the net effect on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A$ (midazolam) and P-glycoprotein (Pgp) (digoxin). At steady state, there was a significant induction of CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4 activities were observed. Pgp activity is significantly inhibited after the first dose, but there was a slight induction at steady state."

Information regarding co-administration with digoxin has been added as follows: "Aptivus, co-administered with low dose ritonavir, may double the exposure of orally administered digoxin at the first dose, whilst the net effect at steady state may rather consist in a slight decrease in digoxin exposure. Monitoring of digoxin serum concentrations is recommended until steady state has been obtained"

Information on midazolam has been included in this section, and states that concomitant use of Aptivus/ritonavir ad oral midazolam is contra-indicated, and states "If Aptivus/ritonavir is administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be instituted and dosage adjustment considered".

There is also additional information on interactions with carbemazepine (see new special warning above). Furthermore information relation to an interaction with theophylline has been updated and it is now advised that theophylline plasma concentrations should be monitored during the first two weeks or co-administration with Aptivus/ritonavir and the theophylline dose should be increased as need.

 

Section 5.1 has bee updated to include information on the correlation between baseline resistance and virological response at 48 weeks.

Updated on 27/06/2007 and displayed until 30/08/2007
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   03/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.4 (Special warnings and special precautions for use) has been updated with regard to the advice for liver function monitoring, and the advice not to use in treatment naive patients has been reinforced with additional information regarding an increased risk of significant transaminase elevations when Aptivus/ritonavir combination was used in this patient group. In addition, information regarding the risk of osteonecrosis in patients with advanced HIV-disease and/or long term exposure to combination antiretroviral therapy has been added and this section now also advises that in in vitro experiments tipranavir was observed to inhibit human platelets aggregation at levels consistent with exposures observed in patients receiving Aptivus/ritonavir.

 

Section 4.8 (Undesirable effects) has been updated with information from the 48 week analyses of the pivotal RESIST-1 and RESIST-2 clinical trials. Previously only data for the 24 week analyses was available and thus the incidence rates of some adverse events have been updated with the 48 week data. Hyperbilirubinaemia (rare) has been added to the list of adverse events and this section now also provides information regarding the risk of osteonecrosis in patients with advanced HIV-disease and/or long term exposure to combination antiretroviral therapy.

 

Section 5.1 (Pharmacodynamic properties) has been updated with data from the 48 week analyses of the pivotal RESIST-1 and RESIST-2 clinical trials.

Updated on 25/01/2007 and displayed until 27/06/2007
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   11/2006
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.5 has been updated with the following information regarding concomitant use of trazodone: "In a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increased plasma concentration of trazodone (AUC increased by 2.4 fold). Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir in this study. However, it is unknown whether the combination of tipranavir/ritonavir might cause a larger increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered."

Section 5.1 has been updated with information regarding the in vitro antiviral activity of Aptivus.

Updated on 03/11/2006 and displayed until 25/01/2007
Reasons for adding or updating:
  • 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 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   11/2006
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Section 4.8 (undesirable effects) has been updated with information regarding increased risk of bleeding and the occurrence of fatal and non fatal intracranial haemorrhage, as follows:

 

“Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving APTIVUS, many of whom had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. However, in some cases the role of APTIVUS cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.

 

“An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the APTIVUS clinical trials.”

 

Section 4.4 (Special warnings and special precautions for use) has been updated to include information regarding bleeding, previously only stated in Section 4.8, and intracranial haemorrhage, as above, and also includes the following statement:

 

“APTIVUS, co-administered with low dose ritonavir, should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants.”

 

Section 4.5 (Interactions with other medicinal products and other forms of interaction) has been updated with new information regarding interactions with methadone and atazanavir:

 

“Narcotic analgesics (Methadone/Meperidine): Co-administration of APTIVUS and low dose ritonavir with single dose methadone was demonstrated to decrease methadone pharmacokinetic parameters (AUC0-24h ratio of 0.47 with 90% CI [0.44; 0.51] and Cmax ratio of 0.45 with 90% CI [0.41; 0.49]), in a study conducted in fasted healthy subjects.  Therefore in such cases, patients should be monitored for opiate withdrawal syndrome.  Dosage of methadone may need to be increased.”

And:

 

“Co-administration of Tipranavir/ritonavir and Atazanavir/ritonavir:

In a study performed in healthy volunteers co-administration of atazanavir 300 mg with TPV/r 500/100 mg bid resulted on one hand in a marked increase of Tipranavir exposure (notably Cp12h ratio of 1.75 with 90% CI [1.39-2.20]) and ritonavir exposure (AUC ratio of 1.51 with 90% CI [1.24-1.83] and Cmax ratio of 1.38 with 90% CI [1.13-1.67]) associated with a risk of over-toxicity and on the other hand on a marked decrease of atazanavir exposure associated with a risk of loss of efficacy (AUC0-24h ratio of 0.32 with 90% CI [0.29-0.36], Cmax ratio of 0.43 with 90% CI [0.38-0.50] and Cp24h ratio of 0.19 with 90% CI [0.15-0.24]).

 

“Consequently, this co-administration is not recommended.  If the co-administration is nevertheless considered necessary, a close monitoring of the safety of tipranavir and a monitoring of plasma concentrations of atazanavir are strongly encouraged.”

Updated on 19/01/2006 and displayed until 03/11/2006
Reasons for adding or updating:
  • New SPC for new product

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Active Ingredients

 
   Tipranavir