Gilead Sciences Ltd

Update to:

4.4       Special warnings and precautions for use

Minor correction to Renal Impairment statement (page 6 of SPC)

Renal impairment: Atripla is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).

In previous SPC update this read (creatinine clearance < 30 ml/min) which was incorrect.

 

4.6         Fertility, pregnancy and lactation – in particular the efavirenz section

The following is a summary of main amendments/inclusions to the:

SPC:

• Section 3 - Pink, capsule‑shaped, film‑coated tablet, of dimensions 20 mm x 10.4 mm, debossed with “123” on one side, plain on the other side.

• Section 4.1 – Update to indication statement to: ‘Atripla is a fixed‑dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate.  It is indicated for the treatment of human immunodeficiency virus‑1 (HIV‑1) infection in adults aged 18 years and over with virologic suppression to HIV‑1 RNA levels…….’

   

  • Section 4.2 – additional statements for the Posology section - inclusion of paragraphs describing what to do when a dose of Atripla is missed or when a patient vomits within an hour of taking the tablet and amendment to statements on discontinuation of therapy.

   

  • Section 4.4 – Inclusion of statement: ‘Bone: In a 144‑week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral‑naïve patients, small decreases in bone mineral density of the hip and spine were observed in both treatment groups.  Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks.  Decreases in bone mineral density of the hip were significantly greater in this group until 96 weeks.  However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.’

  Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8).  If bone abnormalities are suspected then appropriate consultation should be obtained.

   

  • Section 4.6 – Now titled ‘Fertility, pregnancy and lactation’ – within this section amendments to the Pregnancy, Breast-feeding & Fertility statements: including:

   

  Emtricitabine and tenofovir disoproxil fumarate: A moderate amount of data on pregnant women (between 300‑1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil fumarate.  Animal studies on emtricitabine and tenofovir disoproxil fumarate do not indicate reproductive toxicity (see section 5.3).

   

  Atripla should not be used during pregnancy unless clearly necessary (there are no other appropriate treatment options).

   

  Breast‑feeding

  Emtricitabine and tenofovir have been shown to be excreted in human milk.  There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants.  Studies in rats have demonstrated that efavirenz is excreted in milk; concentrations of efavirenz were much higher than those in maternal plasma.  Therefore Atripla should not be used during breast-feeding.

   

  As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant.

   

  Fertility

  No human data on the effect of Atripla are available.  Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil fumarate on fertility.

   

   

  • Section 5.1 - Inclusion of statement ‘Paediatric population: The safety and efficacy of Atripla in children under the age of 18 years have not been established.’

   

  • Section 5.2 – Inclusion of statements on Gender, Ethnicity and paediatric populations

   

  • Section 5.3 – Inclusion of information on pre-clinical safety data

   

  • Section 10 – Change to date of revision

Change to:

Section 4.8:           update for the efavirenz component is consistent with the SPC proposed in the Sustiva Type II variation procedure EMEA/H/C/249/II/104 (submission date, 18 December 2009). Correspondingly, the update for the tenofovir disoproxil (as fumarate) and emtricitabine components is consistent with the SPC proposed for Truvada Type II variation procedure EMEA/H/C/594/II/54 (submission date, 13 March 2009).


Section 10:  Change of Date or Revision to December 2010

Update to Section 5.1 to include data from the Kaiser Observational Study: Please see below:

A similar trend was observed in a sub-group analysis of treatment-experienced patients with baseline HIV‑1 RNA < 75 copies/ml from a retrospective cohort study (data collected over 20 months, see Table 7).

Table 7: Maintenance of pure virologic response (Kaplan Meier % (Standard Error) [95%CI]) at week 48 for treatment-experienced patients with baseline HIV‑1 RNA < 75 copies/ml who had therapy switched to Atripla according to the type of prior antiretroviral regimen (Kaiser Permanente patient database)

Section 7:

been updated to reflect the change of address of the EU Marketing Authorisation Holder for Atripla from Dublin to Cork.

Section 10:

Date of revision changed to August 09.

• In section 6.3, the shelf-life has been changed from 2 to 3 years.

• In section 10, the date of revision of the text has been updated to March 2009

Section 4.1

Statement regarding demonstration of benefit being based on 48-week data rather than 24-week data.

Section 4.4

Addition of the following statements:

• Currently available data indicate a trend that in patients on a PI‑based antiretroviral regimen the switch to Atripla may lead to a reduction of the response to the therapy (see section 5.1).  These patients should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions.
• Atripla should not be administered concomitantly with adefovir dipivoxil.
• Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8). 

Update to the section on co-infection with HBV or HCV.

Section 4.5

Updated to include adefovir dipivoxil.

Section 4.8

Extensive changes made to the information at the beginning of the section relating to adverse reactions reported in the 48 week study AI266073 including the addition of a new table (Table 2) for this study and subsequent renumbering of later tables.

The following statement added under Adverse reactions associated with individual components of Atripla

• The most notable adverse reactions that have been reported in clinical studies with efavirenz are rash and nervous system symptoms.  The administration of efavirenz with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see section 4.4).  There have been post-marketing reports in association with tenofovir disoproxil fumarate of renal and urinary disorders including renal failure, proximal tubulopathy (including Fanconi syndrome), acute tubular necrosis and nephrogenic diabetes insipidus.

The following adverse reactions added:

• Cerebellar coordination and balance disturbances, rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, hypokalaemia, hepatic steatosis,  (all frequency not known)

The following statement has also been added:

·         The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy and hypophosphataemia.  These events are not considered to be causally associated with tenofovir disoproxil fumarate therapy in the absence of proximal renal tubulopathy.

Section 5.1

In vivo resistance updated from none to extremely limited

The Clinical experience information relating to Study AI266073 has been extensively updated to reflect the 48-week data rather than 24-week data.

Section 10

Date of revision updated to 12/2008