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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 100 mg/ml oral solution

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:   25-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 6.5 - Nature and contents of container
  • 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 6.5

Amended from:

Amber glass bottle, with two-piece child-resistant closure (outer shell high density polyethylene (HDPE), inner shell polypropylene with a foamed low density polyethylene (LDPE)/HDPE liner). Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml oral syringe, polypropylene syringe cap and clear LDPE bottle-syringe adapter.


to:

Amber glass bottle, with two-piece plastic child-resistant closure (outer shell high density polyethylene (HDPE), inner shell polypropylene resin with a foamed laminated polyethylene liner. Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml oral syringe, HDPE syringe tip cap and clear LDPE bottle-syringe adaptor.

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 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 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • 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 4.1

Aptivus 100 mg/ml oral solution co-administered with ……

 

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

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.

Paediatric population

 

……

 

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.


Patients with liver impairment amended to Liver Impairment.

Patients with renal impairment amended to Renal Impairment.

 

Paediatric population

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

 

Various 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 one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus oral solution in mostly treatment-experienced children aged 2 to 12 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 6.5

5 ml dispensing syringe amended to 5 ml oral syringe.

 

Section 6.6

Where the word “syringe” is mentioned in this section it is amended to “oral syringe”

 

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 4.7 - 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 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 4.7
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
Adverse Events 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 information added.

Section 5.2
Minor change to amend elderly to 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
  • Change to section 10 - Date of revision of the text
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.

Section 10
Date of Revision amended.
Updated on 10/06/2013 and displayed until 21/01/2014
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
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 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 03/08/2011 and displayed until 18/01/2012
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 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
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 03/08/2011
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 4.6 - 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 ....."
Title of Paediatrics amended to Paediatric popution.
Information regarding use in children under 2 - minor editorial changes.
Addition of Paragraph Method of Administration - regarding taking with food at end of this section.

Section 4.4

Sentence "Therfore tipranavir with ritonavir should not be used in treatment-naive patients."

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 24/02/2010 and displayed until 28/10/2010
Reasons for adding or updating:
  • New SPC for new product
Date of revision of text on the SPC:  
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

None provided

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Active Ingredients

 
   Tipranavir