Viread 245 mg film-coated tablets

Update to section 4.4 and 4.6 of the SmPC to implement modifications of the HIV SmPC/PL to update wording related to the risk of HIV transmission in accordance with the January 2022 CHMP adoption of an update to the Product Information for all approved HIV products, recommending the removal of the disease information relating to sexual transmission of HIV and amendment of the sections relating to breast-feeding.

Update to section 2 of the PIL to reflect the changes made to the SmPC.

Update to section 4.4 and 4.6 of the SmPC to implement modifications of the HIV SmPC/PL to update wording related to the risk of HIV transmission in accordance with the January 2022 CHMP adoption of an update to the Product Information for all approved HIV products, recommending the removal of the disease information relating to sexual transmission of HIV and amendment of the sections relating to breast-feeding.

Update to section 2 of the PIL to reflect the changes made to the SmPC.

Following submission of the Viread PSUR (reporting period 01 April 2018 to 31 March 2019), the PRAC adopted a recommendation to amend the SmPC as follows:

• Update of section 4.4 to remove the description of the warnings regarding the co-administration of tenofovir disoproxil and didanosine.
• Update of section 4.5 to replace the wording location of the interaction between tenofovir disoproxil and didanosine.
• Update of section 4.6 to add the main safety results from the main studies with tenofovir disoproxil in the prevention of Mother-To-Child transmission of HBV infection.
• Update of section 4.8 to add a paragraph describing the features of cases of lactic acidosis reported with tenofovir disoproxil and remove the warnings regarding the co-administration of tenofovir disoproxil and didanosine.

No updates to the package leaflet were necessary as a result of these changes.

Sections 4.4 and 5.1 of the products SmPC have been updated with final safety data from Study GS-US-104-0352.

Approval of MA Transfer application changing the Viread MA Holder (MAH) from Gilead Sciences International Ltd., Cambridge - UK (GSIL; ‘transferor’) to Gilead Sciences Ireland UC, Cork - Ireland (GSIUC; ‘transferee’) as a result of ‘BREXIT’. The full details of the new MAH is:

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

The application updates the product information annexes as follows:

• Updates to the Summary of Product Characteristics (SmPC) Section 7 (Marketing Authorisation Holder),
• Updates to Annex IIIA Section 11 (Name and Address of the Marketing Authorisation Holder),
• Updates to Patient Information Leaflet (PIL) Section 6 (Contents of the pack and other information; Marketing Authorisation Holder) and PIL Section 6 Legal Representative details (change of contact information for Ireland, Bulgaria, Croatia, Hungary, Malta, Romania and Slovenia) - with regards to the provision of scientific service.

·         Section 4.4 of  

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

·         Section 4.8 and 5.1 
 

o    based on the final CSR (240 weeks) for Study GS-US-174-0121; a study evaluating the antiviral efficacy, safety and tolerability of tenofovir disoproxil fumarate (DF) monotherapy vs emtricitabine (FTC) plus tenofovir DF fixed-dose combination therapy in subjects with chronic hepatitis B who are resistant to lamivudine (LAM

·         Update to section 4.4 of the SmPC “Special warnings and precautions for use” to revise the wording regarding the risk of sexual transmission of HIV infection following CHMP request adopted in December 2013.

·         Update to section 4.2 of the 245mg SmPC to allow daily dose adjustment in renal impairment

·         Section 5.1- Include the 288 week efficacy and resistance data from studies GS-US-174-0102 & GS-US-174-0103

·         Section 5.2- Update to incorporate minor correction of the “AUC” wording

·         Section 10- Date changed for the revision of the text

·         Sections 4.8 & 5.1- Longer term (168 weeks) safety and efficacy data from study GS-US-174-0108 

·         Section 4.8- Update to the reporting of suspected adverse reactions section

·         Section 5.3- Addition of statement ‘The active substance tenofovir disoproxil fumarate and its main transformation products are persistent in the environment’ as previously agreed with the EMA / CHMP

·         Section 10- Date changed for the revision of the text

- 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 4.1:

Inclusion of the following:

• include a new indication for the treatment of patients chronically infected with hepatitis B virus resistant to lamivudine.

Section 4.8

Patients with lamivudine‑resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil fumarate were identified from a randomised, double-blind study (GS‑US‑174‑0121) in which 280 lamivudine‑resistant patients received treatment with tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 96 weeks.

Section 5.1

Inclusion of text describing the data for 'Experience in patients with lamivudine‑resistant chronic hepatitis B at 96weeks'

Section 10

Date changed to 04/2013 

In section 4.8 (undesirable effects) the following statement now states:

·        
The adverse reactions observed with continued treatment for 240 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. (192 weeks replaced with 240)

In section 5.1:

• The 5 year efficacy and safety data from long term studies ‘0102 and ‘0103 has been included here.

In section 10:

• the date of revision has been updated to January 2012

1. Administrative changes throughout the Viread SPC

2. Changes to the qualitative and quantitative composition section to now state “Each film-coated tablet contains 245mg of tenofovir disoproxil (as fumarate)” (Section 2)

3. In the therapeutic indications, removal of wording “aged 18 years and over” (Section 4.1)

4. Date changed for the latest renewal of authorisation (Section 9)

5. Date changed for the revision of the text (Section 10)

Update to:

Section 3 – inclusion of statement of ‘dimensions 16.8 mm x 10.3 mm’

Section 4.1 – Update to indication statement to Viread is indicated in combination with other antiretroviral medicinal products for the treatment of HIV‑1 infected adults aged 18 years and over.

Section 4.2 – additional statements and amendments for the Posology section including:

Paediatric population: Viread is not recommended for use in children.

The clinical data available in HIV‑1 infected adolescents are inadequate to support the use of tenofovir disoproxil fumarate in this population (see sections 4.4 and 5.1) and no data are currently available in younger children.

No data are currently available in paediatric patients infected with chronic hepatitis B.

Section 4.4 – additional statements and amendments

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 300-1000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil fumarate. 

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of tenofovir disproxil fumurate may be considered during pregnancy, if necessary.

Breast‑feeding

Tenofovir has been shown to be excreted in human milk.  There is insufficient information on the effects of tenofovir in newborns/infants.  Viread should not be used during breast-feeding. 

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

Fertility

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

Age: Pharmacokinetic studies have not been performed in the elderly (over 65 years of age).

Gender: Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.

Ethnicity: Pharmacokinetics have not been specifically studied in different ethnic groups.

Section 5.3 –

Non-clinical safety pharmacology studies reveal no special hazard for humans.  Repeat‑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. 

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice.  These tumours are unlikely to be of relevance to humans. 

Reproductive studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters.  However tenofovir disoproxil fumarate reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.

• Section 4.8: Undesirable effects – addition of the following statement ‘The adverse reactions observed with continued treatment for 192 weeks were consistent with the safety profile of tenofovir disoproxil fumarate’.

• Section 5.1: Pharmacodynamic properties & Table 4: Efficacy parameters – Inclusion of the 192 week data

This is an update to sections 4.2, 4.4, 4.6, 4.8 5.1, 5.2 and 5.3 of the SPC based on the 48-week results from study GS-US-104-0321 in treatment-experienced adolescents aged 12 to 18 years old:

Section 4.2

Inclusion of statement:

"The clinical data available in HIV‑1 infected adolescents are inadequate to support the use of tenofovir disoproxil fumarate in this population (see sections 4.4 and 5.1) and no data are currently available in younger children.

No data are currently available in paediatric patients infected with chronic hepatitis B".

Section 4.4

Inclusion of statement:

"Paediatric population: Viread may cause a reduction in BMD.  The effects of tenofovir disoproxil fumarate‑associated changes in BMD on long‑term bone health and future fracture risk are currently unknown (see section 5.1)".

Section 4.6

Inclusion of statement:

Fertility

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

Section 4.8

Inclusion of statement:

Assessment of adverse reactions is based on one randomised trial (study GS‑US‑104‑0321) in 87 HIV‑1 infected adolescent patients (aged 12 to < 18 years) who received treatment with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with other antiretroviral agents for 48 weeks (see section 5.1).

Section 5.1

Inclusion of summary for study GS‑US‑104‑0321

Section 5.2

Paediatric population

Steady‑state pharmacokinetics of tenofovir were evaluated in 8 HIV‑1 infected adolescent patients (aged 12 to < 18 years) with body weight ≥ 35 kg.  Mean (± SD) C_max and AUC_tau are 0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg·h/ml, respectively.  Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg (as fumarate) was similar to exposures achieved in adults receiving once‑daily doses of tenofovir disoproxil 245 mg (as fumarate).

Pharmacokinetic studies have not been performed in children under 12 years or with renal impairment.

Section 10

Change of revision date to 03/2011

Section 4.1 - Addition of new indication:

• decompensated liver disease

Section 4.4 (Liver Disease):

• Safety and efficacy data are very limited in liver transplant patients.
• There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a Child‑Pugh‑Turcotte (CPT) score > 9.  These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions.  Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

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 ‘B’ contains the following statement in accordance with the new decompensated liver indication:

‘Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was assessed in a double‑blind active controlled study (GS‑US‑174‑0108) in which patients received treatment with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir‑containing arms and the entecavir arm. Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see section 4.4).

Hepatocellular carcinoma was diagnosed in 3 patients in the tenofovir disoproxil fumarate group and two patients in the tenofovir disoproxil fumarate group died during the study.’

Section 5.1:

Includes details of ‘Experience in patients with decompensated liver disease at 48 weeks’: Study GS‑US‑174‑0108

Section 10:

Change of date of revision to – 09/2010

Update to section 4.8 and 5.1:

• to reflect the 144 week data from studies GS-US-174-0102 and GS-US-174-0103 in hepatitis B infected patients

Update to section 10:

Change to date of revision: 04/2010

Update of section 6.3

• to reflect the extension of the shelf-life of the finished product, as packaged for sale, from 36 months to 48 months for Viread

Update to Section 10

• Change to date of revision of text: to 07/2009

Update to Section 4.8:

• to reflect the 96 weeks data from studies GS-US-174-0102 and GS-US-174-0103 in hepatitis B infected patients.

Update to Section 5.1:

• to reflect the 96 weeks data from studies GS-US-174-0102 and GS-US-174-0103 in hepatitis B infected patients.
• to reflect the 48 weeks data from study GS-US-174-0106, in hepatitis B infected patients receiving adefovir dipivoxil with persistent viral replication.

Update to Section 10:

• Date of revision of text to April 2009

Section 4.4

Update to the statement in the SPC regarding bone effects to indicate that bone abnormalities associated with proximal renal tubulopathy may infrequently contribute to fractures. This update was based on a cumulative review of fractures and other unlisted bone events.

Re-ordering of the adverse reactions under renal and urinary disorders under post-marketing experience in terms of seriousness in accordance with The Guideline on Summary of Product Characteristics (October 2005).

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 to section 4.8 for consistency as the event was already included in the section 4.4 of the SPC. The other additions were made following cumulative reviews on hypokalaemia, fractures and other unlisted bone events, and muscle events associated with proximal renal tubulopathy.

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.

The major change is to include a new therapeutic indication for the treatment of chronic Hepatitis B in adults.  The full indication is shown below.

Change to Section 4.1 - Therapeutic indications

Hepatitis B infection: Viread is indicated for the treatment of chronic hepatitis B in adults with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

This indication is based on histological, virological, biochemical and serological responses mainly in adult nucleoside-naïve patients with HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver function.

As a result of this new indication the following sections of the SmPC 4.2, 4.4, 4.5,4.8 5.1 and 5.2 have been changed to reflect new warnings, efficacy and safety information with regard to the treatment of Hepatits B.