Gilead Sciences Ltd

Update to:

• Section 3 – inclusion of statement ‘of dimensions 19 mm x 8.5 mm’

• Section 4.1 – Update to indication statement to ‘Truvada is a fixed dose combination of emtricitabine and tenofovir disoproxil fumarate.  It is indicated in antiretroviral combination therapy for the treatment of HIV‑1 infected adults aged 18 years and over.

• Section 4.2 – additional statements for the Posology section

• Section 4.4 – inclusion of a statement to the section on Co-administration of other medicinal products

Section 4.6 – Now titled ‘Fertility, pregnancy and lactation’

Update to the information in this section

Pregnancy

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).  Therefore the use of Truvada may be considered during pregnancy, if necessary.

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.  Therefore Truvada should not be used during breast-feeding.

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

Fertility

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

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

Section 5.2

Inclusion of the following:

Gender: Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

Ethnicity: No clinically important pharmacokinetic difference due to ethnicity has been identified for emtricitabine.  The pharmacokinetics of tenofovir have not been specifically studied in different ethnic groups.

Paediatric population: In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults.  Pharmacokinetic studies have not been performed with tenofovir in children and adolescents (under 18 years of age).

Section 5.3

Tenofovir disoproxil fumarate: Non‑clinical safety pharmacology studies on tenofovir disoproxil fumarate reveal no special hazard for humans.  Repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration.  Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs).  The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5‑fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40‑fold the exposure in patients).  Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes.  However, it was negative in an in vivo mouse bone marrow micronucleus assay.

Change to:

• Section 4.4 – with an additional warning about hepatic events as a manifestation of Immune Reconstitution syndrome in HIV infected patients co-infected with HBV
• Deletions of all references to "zalcitabine" in Sections 4.4 and 5.1 of the SPC
• Section 4.5 - has been reformatted
• Section 10 - Change to date of revision to 11/2010

Update to

Section 4.4: Include the statement - 

Elderly: Truvada has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with Truvada.

Section 4.5: Include statement - 

As a fixed combination, Truvada should not be administered concomitantly with other medicinal products containing any of the components, emtricitabine or tenofovir disoproxil fumarate (Viread, Emtriva or Atripla).

Truvada should not be administered concomitantly with adefovir dipivoxil.

Section 4.8:

This section has been completely modified. It includes a section on:

a) Summary of the safety profile

b) Tabulated Summary of Adverse Reactions

c) Description of selected adverse reactions

d) Paediatric population

e) Other special population(s)

Section 10:

Change of date of revision to – 08/2010

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 February 2005

Date of latest renewal: 20 January 2010

10.     DATE OF REVISION OF THE TEXT

01/2010

• In section 6.3, the shelf-life has been changed from 3 to 4 years

• In section 10, the date of revision has been changed to 05/2009

Section 4.4

Update to the statement regarding bone effects to indicate that bone abnormalities associated with proximal renal tubulopathy may infrequently contribute to fractures. 

Update to the statement regarding post-treatment exacerbations of hepatitis following discontinuation of therapy. This includes addition of a recommendation not to discontinue Truvada in patients with cirrhosis or advanced liver disease since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Update of the term Pneumocystis carinni pneumonia to Pneumocystis jiroveci pneumonia which is a more medically accepted term.

Section 4.8

Inclusion of hypokalaemia, hepatic steatosis, rhabdomyolysis, and muscular weakness and inclusion of wording to indicate that osteomalacia may be manifested as bone pain and infrequently contribute to fractures. Hepatic steatosis has been added for consistency as the event was already included in the section 4.4.

Inclusion of additional explanatory text to indicate that the adverse reactions of rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy, and hypophosphatemia may occur as a consequence of proximal renal tubulopathy and that these events are not considered to be causally associated with tenofovir disoproxil fumarate (tenofovir DF) therapy in the absence of proximal renal tubulopathy.

Section 4.5 updated to include additional warnings and precautions.  Section 7 updated to reflect MAH post code change.