$0·Section 4.4 Special warnings and precautions foruse - reference co-administration with TAF$0$0·Section 4.5 Interaction with other medicinalproducts and other forms of interaction - reference co-administration with TAF $0

·         Section 4.4

 

o    Revise the HIV class label wording on mitochondrial dysfunction following the review of existing data on mitochondrial toxicity including the Mitochondrial Toxicity in Children (MITOC) Study

o    The PILs were also updated accordingly

 

·         Sections 4.4 and 4.5  

o     Addition of a warning update to the safety information with the potential drug interaction of ledipasvir/sofosbuvir (LDV/SOF), as well as that of LDV and SOF as single agents with tenofovir disoproxil fumarate

o    The PILs were also updated accordingly

 

Sections 4.4 & 4.8:

- Update to delete previous lipodystrophy class labelling text and, to add new class labelling regarding weight and metabolic parameters (blood lipids and glucose).

Section 10:

- Change to the date of revision to January 2016.

Section 4.4:

- Inclusion to state that the most pronounced decreases in bone mineral density were seen in patients treated with tenofovir DF as part of a regimen containing a boosted protease inhibitor, and also to advise that alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures, in line with HIV European guidelines.

Section 10:

- Change to the date of revision to December 2015.

Sections 4.5:

- Information that co-administration of simeprevir with efavirenz is not recommended. The interactions table has also been updated to reflect the observed lack of clinically relevant interaction between simeprevir and tenofovir, and the expected lack of interaction between simeprevir and emtricitabine

Section 10:

- Change to the date of revision to June 2015

Sections 4.4 & 4.8:

- Removal of the warnings related to lactic acidosis

Section 10:

- Change to the date of revision to May 2015

Section 5.1:

- Inclusion of a reference to the tenofovir resistance-associated substitution K70E.

Section 10:

- Change to the date of revision to December 2014.

Section 4.4 of the SmPC:

- Addition of safety information on the risk of renal injury in patients with risk factors for renal dysfunction after co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) with tenofovir.
- Change of wording around the monitoring of renal function “In patients at risk for renal impairment consideration should be given to a more frequent monitoring of renal function is required.”/ “Interrupting treatment with Atripla should also be considered in case of progressive decline of renal function when no other cause has been identified.”

Section 4.8 of the SmPC:

- Addition of information about proximal renal tubulopathy.

• Update to section 4.6 to incorporate the efavirenz pregnancy registry data

• Change to the date of revision in section 10 to July 2014

• Update to section 4.5 around cannabinoid tests interaction

• Change to the date of revision to May 2014 in section 10

• Update of section 4.5 on interactions with artemether/lumefantrine

• Update of section 4.6 with information on the excretion of efavirenz (EFV) into human breast milk and other minor changes for consistency

• Update of section 10 with the new date of revision

Section 4.5:

·         Information on the drug-drug interaction with the HCV protease inhibitors boceprevir and telaprevir

 

·         Additional information on the interaction with rifabutin

·         Sections 4. 4 and 4.5 - concomitant use of Ginkgo biloba extracts is not recommended

 

·         Change to the date of revision in section 10

- Sections 4.4 and 4.8 of the SPC have been updated to include the below wording:

 

·         “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”

 

- Additional changes to sections 4.4 and 4.8 are as follows:

 

• Expression of combination antiretroviral therapy (CART) was amended throughout sections 4.4 and 4.8 of the SPC

 

Section 10

 

- Change to date of revision to May 2013

Section 4.2 (Posology & method of administration)

• Tenofovir exposure (AUC) will be approximately 30% (changed from 35%) lower following administration of Atripla on an empty stomach as compared to the individual component TDF when taken with food

Section 4.4 (Special warnings & precautions for use) 

• Addition to state that Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin

Section 4.5 (Interactions with other medicinal products) 

• Addition to state that Atripla should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin
• Amendment to the biotransformation data on P450 enzymes and also that efavirenz has shown to induce UGT1A1
• Antimalarials, acenocoumarol, norephinephrine and dopamine re-uptake inhibitor interaction data included

Section 4.8 (Undesirable effects) 

• In the metabolism and nutrition disorders section, hypertriglyceridaemia is listed as common and hypercholesterolaemia is listed as uncommon adverse reactions to the efavirenz individual component
• In the hepatobiliary disorders section, elevated aspartate aminotransferase, elevated alanine aminotransferase, elevated gamma-glutamyltransferase listed as common adverse reactions to the efavirenz individual component

Section 5.1 (Pharmacodynamic properties) 

• Inclusion of a paragraph to discuss resistance & 96 week data from the open-label extended phase of study GS‑01‑934

Section 5.2 (Pharmacokinetic properties)  

• Tenofovir exposure (AUC) will be approximately 30% (changed from 35%) lower following administration of Atripla on an empty stomach as compared to the individual component TDF when taken with food
• Amendment to the biotransformation data on P450 enzymes and also that efavirenz has shown to induce UGT1A1
• Change in the effect of food section to state that dosing of TDF and FTC in combination with either a high fat meal or a light meal increased the mean AUC of tenofovir by 43.6% and 40.5%, and C_max by 16% and 13.5%

Section 10 (Date of revision of the text) 

• Date changed for the revision of the text to January 2013

·         Section 6.3- Shelf life extension from 36 to 48 months

·         Section 10- Date changed for the revision of the text to November 2012

·         Section 4.3  - use of word ‘Co-administration instead of administration’

·         Section 4.3  - use of word ‘adverse reactions instead of undesirable effects’

·         Section 6.1 – ‘List of excipients’ – from hydroxypropylcellulose to hyprolose. This is just change in name and not the excipient (also reflected in the PIL)

·         Section 6.5 - addition of new pack size ’90 (3 bottles of 30) film-coated tablets’.

·         Updated to improve clarity and readability

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

 

1)

 

Women of childbearing potential: see below and section 5.3.  Pregnancy should be avoided in women receiving Atripla.  Women of childbearing potential should undergo pregnancy testing before initiation of Atripla.

 

2)

 

Pregnancy

Efavirenz: As of July 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 718 pregnancies with first-trimester exposure to efavirenz-containing regimens, resulting in 604 live births. One child was reported to have a neural tube defect, and the frequency and pattern of other birth defects were similar to those seen in children exposed to non‑efavirenz‑containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5‑1 case per 1,000 live births. In retrospective reports, there have been six cases of findings consistent with neural tube defects including meningomyelocele, all in mothers exposed to efavirenz‑containing regimens in the first trimester. A causal relationship of these events to the use of efavirenz has not been established and the total number of pregnant women exposed to efavirenz-containing regimens is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy.

 

Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3).

 

3)

 

Atripla should not be used during pregnancy unless the clinical condition of the woman requires treatment with efavirenz/emtricitabine/tenofovir disoproxil fumarate.

 

10.     DATE OF REVISION OF THE TEXT

 

11/2011

 

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

section 4.2: revised wording for the dosing recommendation for coadministration with rifampicin

section 4.4: statement on closer monitoring of patients who have previously experienced renal events while receiving adefovir dipivoxil

section 4.5: complete review of interactions section

section 4.6: update to pregnancy data

section 4.8: details of exacerbation of hepatitis after the discontinuation of treatment to the postmarketing experience section and inclusion of the new postmarketing event of angioedema, tinnitus, tremor and flushing.

section 10: Change to date of revision

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)

 

Prior Atripla components (N=299)	Prior NNRTI‑based regimen (N=104)	Prior PI‑based regimen (N=34)
98.9% (0.6%) [96.8%, 99.7%]	98.0% (1.4%) [92.3%, 99.5%]	93.4% (4.5%) [76.2%, 98.3%]

Update to Section 10: Change of date of revision to April 2010

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

Section 4.5 Interaction with other medicinal products and other forms of interaction - addition of tacrolimus interaction information.
Section 4.8 Undesirable effects - revision of information relating to HIV/HBV or HCV co-infected patients relating to data from study GS-01-934 144 week data.
Section 5.1 Pharmacodynamic properties In vivo resistance  - update to information relating to study GS-01-934 144 week data.
Section 8.          MARKETING AUTHORISATION NUMBER(S) - new 90-day pack.

Variation 1A/01 to change the MAH name.