This information is intended for use by health professionals

1. Name of the medicinal product

Lamivudine/Tenofovir disoproxil 300 mg/245 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate equivalent to 245 mg tenofovir disoproxil.

Excipient with known effect

Each film-coated tablet contains 6.58 mg of sodium.

Each film-coated tablet contains 0.245 mg of lecithin (soya).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

White to off white coloured, capsule shaped, biconvex, film coated tablet, with “LT” debossed on one side and plain on other side.

Length: 18.1 mm ± 0.2 mm

Breadth: 8.6 mm ± 0.2 mm

4. Clinical particulars
4.1 Therapeutic indications

HIV-1 infection

Lamivudine/Tenofovir disoproxil tablet is indicated as part of antiretroviral combination therapy for the treatment of HIV-1 infected adults over 18 years of age.

In adults, the demonstration of the benefit of tenofovir disoproxil in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which tenofovir disoproxil was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

The choice of tenofovir disoproxil to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults

The recommended dose of Lamivudine/Tenofovir disoproxil tablet for the treatment of HIV is 300 mg/245 mg (one tablet) once daily taken orally with food.

Separate preparations of lamivudine and tenofovir disoproxil are available for treatment of HIV-1 infection if it becomes necessary to discontinue or modify the dose of one of the components of Lamivudine/Tenofovir disoproxil tablet. Please refer to the Summary of Product Characteristics for these medicinal products.

Paediatric populations

Lamivudine/Tenofovir disoproxil tablet is not recommended for use in children and adolescents below the age of 18 years due to insufficient data on safety and efficacy (see section 5.1).

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years (see section 4.4).

Renal impairment

Lamivudine

Lamivudine concentrations are increased in patients with moderate severe renal impairment due to decreased clearance (see tables).

Tenofovir disoproxil

There are limited data on the safety and efficacy of tenofovir disoproxil in adult patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in adult patients with renal impairment tenofovir disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks.

Dosing recommendations

Creatinine clearance (ml/min)

First dose

Maintenance dose

≥50

300 mg

300 mg once daily

Moderate renal impairment (CrCl 30-49 mL/min)

No data available

Lamivudine/Tenofovir disoproxil tablet are not recommended for use because appropriate dose reductions cannot be achieved with the fixed dose combination.

Severe renal impairment (CrCl < 30 mL/min) and haemodialysis patients

No data available

Lamivudine/Tenofovir disoproxil tablet are not recommended for use because appropriate dose reductions cannot be achieved with the fixed dose combination.

Method of administration

Tablets for oral administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

This medicinal product contains lecithin (soya). If you are allergic to peanut or soya, do not use this medicinal product.

4.4 Special warnings and precautions for use

HIV-1

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) 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.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Renal and bone effects in adults

Lamivudine

In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see section 4.2).

Renal effects

Tenofovir is principally eliminated via the kidneys by a combination of glomerular filtration and active tubular secretion. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinical practice (see section 4.8).

Renal monitoring

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with lamivudine/tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.

Renal management

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any adult patient receiving tenofovir disoproxil, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with lamivudine/tenofovir disoproxil in adult patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).

Interrupting treatment with lamivudine/tenofovir disoproxil should also be considered in case of progressive decline of renal function when no other cause has been identified.

Renal safety with lamivudine/tenofovir disoproxil has not been studied. Renal safety with tenofovir disoproxil has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance < 80 ml/min).

Co-administration and risk of renal toxicity

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If tenofovir disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients (see section 4.5). In patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4 might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).

Adult patients with creatinine clearance < 50 ml/min, including haemodialysis patients

There are limited data on the safety and efficacy of tenofovir disoproxil in patients with impaired renal function. Therefore, tenofovir disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of lamivudine/tenofovir is not recommended.

Bone effects

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8).

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at 144 weeks. Decreases in BMD of 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.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.

Elderly

Tenofovir disoproxil 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 lamivudine/tenofovir disoproxil tablet.

Opportunistic infections

Patients receiving lamivudine/tenofovir disoproxil or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.

Pancreatitis

Cases of pancreatitis have occurred rarely. However it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Liver disease

The safety and efficacy of lamivudine/tenofovir have not been established in patients with significant underlying liver disorders. The pharmacokinetics of lamivudine and tenofovir have been studied in patients with hepatic impairment and no dose adjustment is required.

Patients with hepatitis B or C virus infection

HIV-1 infected patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Discontinuation of lamivudine/tenofovir disoproxil therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue lamivudine/tenofovir disoproxil should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered (see section 4.8).

Safety and efficacy data of tenofovir disoproxil are very limited in liver transplant patients.

There are limited data on the safety and efficacy of tenofovir disoproxil 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.

Exacerbations of hepatitis

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see section 4.8). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.

Co-administration of other medicinal products

- Lamivudine/Tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product (see section 4.5). If concomitant use of Lamivudine/Tenofovir disoproxil and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

- Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in HIV-1 infected patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If Lamivudine/Tenofovir disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

- Lamivudine/Tenofovir disoproxil should not be administered concomitantly with other medicinal products containing tenofovir disoproxil, tenofovir alafenamide, emtricitabine, adefovir dipivoxil or lamivudine.

- A higher risk of renal impairment has been reported in HIV-1 infected patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function is required in these patients (see section 4.5). In HIV-1 infected patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

- Co-administration of tenofovir disoproxil and didanosine is not recommended. Co-administration of tenofovir disoproxil and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

- The combination of lamivudine with cladribine is not-recommended (see section 4.5).

Triple therapy with nucleosides/nucleotides

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil and lamivudine was combined with abacavir or didanosine as a once daily regimen.

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil in the setting of ledipasvir/sofosbuvir or sofosbuvir/velpatasvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/sofosbuvir or sofosbuvir/velpatasvir with tenofovir disoproxil given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir or sofosbuvir/velpatasvir concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.

4.5 Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been conducted using lamivudine and tenofovir disoproxil tablets. Drug interaction studies have been conducted with lamivudine or tenofovir disoproxil, the components of this fixed dose combination.

Interaction studies have only been performed in adults.

Lamivudine

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be avoided.

The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine.

A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine (see section 5.2).

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4).

Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely.

Tenofovir disoproxil

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.

Concomitant use not recommended

Lamivudine and tenofovir disoproxil tablet should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide.

Lamivudine and tenofovir disoproxil tablet should not be administered concomitantly with adefovir dipivoxil.

Didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products

Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

Use of tenofovir disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil.

Other interactions

Interactions between tenofovir disoproxil and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, and once daily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil and other medicinal products

Medicinal product by therapeutic areas

(dose in mg)

Effects on drug levels

Mean percent change in AUC, Cmax, Cmin

Recommendation concerning co-administration with 245 mg tenofovir disoproxil (as fumarate)

ANTI-INFECTIVES

Antiretrovirals

Protease inhibitors

Atazanavir/Ritonavir/Tenofovir disoproxil

(300 q.d./100 q.d./300 q.d.)

Atazanavir:

AUC: ↓ 25%

Cmax: ↓ 28%

Cmin: ↓ 26%

Tenofovir:

AUC: ↑ 37%

Cmax: ↑ 34%

Cmin: ↑ 29%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir-associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).

Lopinavir/Ritonavir/Tenofovir disoproxil

(400 b.i.d./100 b.i.d./300 q.d.)

Lopinavir/ritonavir:

No significant effect on lopinavir/ritonavir PK parameters.

Tenofovir:

AUC: ↑ 32%

Cmax: ↔

Cmin: ↑ 51%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir-associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).

Darunavir/Ritonavir/Tenofovir disoproxil

(300/100 b.i.d./300 q.d.)

Darunavir:

No significant effect on darunavir/ritonavir PK parameters.

Tenofovir:

AUC: ↑ 22%

Cmin: ↑ 37%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir-associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).

NRTIs

Didanosine/Tenofovir disoproxil

Co-administration of tenofovir disoproxil and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.4).

Adefovir dipivoxil/Tenofovir disoproxil

AUC: ↔

Cmax: ↔

Tenofovir disoproxil should not be administered concurrently with adefovir dipivoxil (see section 4.4).

Entecavir/Tenofovir disoproxil

AUC: ↔

Cmax: ↔

No clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with entecavir.

Hepatitis C virus antiviral agents

Ledipasvir/Sofosbuvir

(90 mg/400 mg q.d.) +

Atazanavir/Ritonavir

(300 mg q.d./100 mg q.d.) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)1

Ledipasvir:

AUC: ↑ 96%

Cmax: ↑ 68%

Cmin: ↑ 118%

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↑ 42%

Atazanavir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 63%

Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 45%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 47%

Cmin: ↑ 47%

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, ledipasvir/sofosbuvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Ledipasvir/Sofosbuvir

(90 mg/400 mg q.d.) +

Darunavir/Ritonavir

(800 mg q.d./100 mg q.d.) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)1

Ledipasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Sofosbuvir:

AUC: ↓ 27%

Cmax: ↓ 37%

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Darunavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 48%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 50%

Cmax: ↑ 64%

Cmin: ↑ 59%

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, ledipasvir/sofosbuvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Ledipasvir/Sofosbuvir

(90 mg/400 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

(600 mg/200 mg/300 mg q.d.)

Ledipasvir:

AUC: ↓ 34%

Cmax: ↓ 34%

Cmin: ↓ 34%

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98%

Cmax: ↑ 79%

Cmin: ↑ 163%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Ledipasvir/Sofosbuvir

(90 mg/400 mg q.d.) +

Emtricitabine/Rilpivirine/Tenofovir disoproxil

(200 mg/25 mg/300 mg q.d.)

Ledipasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↔

Cmin: ↑ 91%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Ledipasvir/Sofosbuvir (90 mg/400 mg q.d.) +

Dolutegravir (50 mg q.d.) +

Emtricitabine/Tenofovir disoproxil (200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072

AUC: ↔

Cmax: ↔

Cmin: ↔

Ledipasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Dolutegravir

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 65%

Cmax: ↑ 61%

Cmin: ↑ 115%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Atazanavir/Ritonavir

(300 mg q.d./100 mg q.d.) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↑ 42%

Velpatasvir:

AUC: ↑ 142%

Cmax: ↑ 55%

Cmin: ↑ 301%

Atazanavir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 39%

Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 29%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 55%

Cmin: ↑ 39%

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Darunavir/Ritonavir

(800 mg q.d./100 mg q.d.) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↓28%

Cmax: ↓ 38%

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Velpatasvir:

AUC: ↔

Cmax: ↓ 24%

Cmin: ↔

Darunavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 55%

Cmin: ↑ 52%

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Lopinavir/Ritonavir

(800 mg/200 mg q.d.) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↓ 29%

Cmax: ↓ 41%

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Velpatasvir:

AUC: ↔

Cmax: ↓ 30%

Cmin: ↑ 63%

Lopinavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 42%

Cmin: ↔

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and lopinavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Raltegravir (400 mg b.i.d) +

Emtricitabine/Tenofovir disoproxil

(200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Velpatasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Raltegravir:

AUC: ↔

Cmax: ↔

Cmin: ↓ 21%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 46%

Cmin: ↑ 70%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

(600 mg/200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↑ 38%

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Velpatasvir:

AUC: ↓ 53%

Cmax: ↓ 47%

Cmin: ↓ 57%

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81%

Cmax: ↑ 77%

Cmin: ↑ 121%

Concomitant administration of sofosbuvir/velpatasvir and efavirenz is expected to decrease plasma concentrations of velpatasvir. Co-administration of sofosbuvir/velpatasvir with efavirenz-containing regimens is not recommended.

Sofosbuvir/Velpatasvir

(400 mg/100 mg q.d.) +

Emtricitabine/Rilpivirine/Tenofovir disoproxil

(200 mg/25 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

Velpatasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40%

Cmax: ↑ 44%

Cmin: ↑ 84%

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Sofosbuvir

(400 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

(600 mg/200 mg/300 mg q.d.)

Sofosbuvir:

AUC: ↔

Cmax: ↓ 19%

GS-3310072:

AUC: ↔

Cmax: ↓ 23%

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25%

Cmin: ↔

No dose adjustment is required.

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provided similar results.

2 The predominant circulating metabolite of sofosbuvir.

Studies conducted with other medicinal products

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.

Tenofovir disoproxil must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

Lamivudine/tenofovir disoproxil can be used during pregnancy if clinically needed.

Lamivudine

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans.

More than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. The malformative risk is unlikely in humans based on those data.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Tenofovir disoproxil

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

Breast-feeding

It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Lamivudine

Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.

Tenofovir disoproxil

Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants.

Fertility

Lamivudine

Studies in animals showed that lamivudine had no effect on fertility (see section 5.3).

Tenofovir disoproxil

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil on fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported with Lamivudine/Tenofovir disoproxil tablets.

4.8 Undesirable effects

Lamivudine

The following adverse reactions have been reported during therapy for HIV disease with lamivudine.

The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Tabulated summary of adverse reactions associated with lamivudine

Frequency

Lamivudine

Blood and lymphatic systems disorders

Uncommon

Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare

Pure red cell aplasia

Metabolism and nutrition disorders

Very rare

Lactic acidosis

Nervous system disorders

Common

Headache, insomnia

Very rare

Peripheral neuropathy (or paraesthesia)

Respiratory, thoracic and mediastinal disorders

Common

Cough, nasal symptoms

Gastrointestinal disorders

Common

Nausea, vomiting, abdominal pain or cramps, diarrhoea

Rare

Pancreatitis, elevations in serum amylase

Hepatobiliary disorders

Uncommon

Transient elevations in liver enzymes (AST, ALT).

Rare

Hepatitis

Skin and subcutaneous tissue disorders

Common

Rash, alopecia

Rare

Angioedema

Musculoskeletal and connective tissue disorders

Common

Arthralgia, muscle disorders

Rare

Rhabdomyolysis

General disorders and administration site conditions

Common

Fatigue, malaise, fever

Description of selected adverse reactions

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4)

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. 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 (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term combined antiretroviral exposure (cART). The frequency of which is unknown (see section 4.4).

Tenofovir disoproxil

Summary of the safety profile

HIV-1 and hepatitis B

In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving tenofovir disoproxil (see section 4.4).

Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events.

Co-administration of tenofovir disoproxil and didanosine is not recommended as this may result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).

Hepatitis B

Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil was nausea (5.4%).

Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4).

Tabulated summary of adverse reactions

Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 3.

HIV-1 clinical studies

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies

Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil. After an initial decline of approximately -4.9 ml/min (using Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation).

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

In the tenofovir disoproxil 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. After 168 weeks, 16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% (2/22) in the entecavir group.

Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see section 4.4).

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil (n = 141) or emtricitabine/tenofovir disoproxil (n = 139) for 240 weeks.

The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 3: Tabulated summary of adverse reactions associated with tenofovir disoproxil based on clinical study and post-marketing experience

Frequency

Tenofovir disoproxil

Metabolism and nutrition disorders:

Very common:

hypophosphataemia1

Uncommon:

hypokalaemia1

Rare:

lactic acidosis

Nervous system disorders:

Very common:

dizziness

Common:

headache

Gastrointestinal disorders:

Very common:

diarrhoea, vomiting, nausea

Common:

abdominal pain, abdominal distension, flatulence

Uncommon:

pancreatitis

Hepatobiliary disorders:

Common:

increased transaminases

Rare:

hepatic steatosis, hepatitis

Skin and subcutaneous tissue disorders:

Very common:

rash

Rare:

angioedema

Musculoskeletal and connective tissue disorders:

Uncommon:

rhabdomyolysis1, muscular weakness1

Rare:

osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 2, myopathy1

Renal and urinary disorders:

Uncommon:

increased creatinine, proximal renal tubulopathy (including Fanconi syndrome)

Rare:

acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus

General disorders and administration site conditions:

Very common:

asthenia

Common:

fatigue

1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.

2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the tenofovir disoproxil expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access program (n = 7,319).

Description of selected adverse reactions

HIV-1 and hepatitis B

Renal impairment

As tenofovir disoproxil may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

HIV-1

Interaction with didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

Hepatitis B

Exacerbations of hepatitis during treatment

In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

Exacerbations of hepatitis after discontinuation of treatment

In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see section 4.4).

Other special population(s)

Elderly

Tenofovir disoproxil 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 tenofovir disoproxil (see section 4.4).

Renal impairment

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with tenofovir disoproxil (see sections 4.2, 4.4 and 5.2). The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Lamivudine

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose.

Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.

Tenofovir disoproxil

Symptoms

If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), and standard supportive treatment applied as necessary.

Management

Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. It is not known whether tenofovir can be removed by peritoneal dialysis.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC code: J05AR12

Mechanism of action

Lamivudine

Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro; it is also active against zidovudine-resistant clinical isolates of HIV.

No antagonistic effects in vitro were seen with lamivudine and other anti retrovirals (tested agents: abacavir, didanosine, nevirapine and zidovudine).

Tenofovir disoproxil

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β, and γ. At concentrations of up to 300 µmol/l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays.

Data pertaining to HIV

HIV antiviral activity in vitro

The concentration of tenofovir required for 50% inhibition (EC50) of the wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells. Tenofovir shows activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells.

Resistance

Lamivudine

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (RT). This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.

In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTI's should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTI's are available.

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardised and results may vary according to methodological factors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro.

Tenofovir disoproxil

Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety). Tenofovir disoproxil should be avoided in antiretroviral experienced patients with strains harbouring the K65R mutation (see section 4.4). In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir disoproxil 245 mg (as fumarate) against strains of HIV-1 with resistance to nucleoside inhibitors. The results indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced response to tenofovir disoproxil 245 mg (as fumarate) therapy.

Clinical efficacy and safety

Lamivudine

In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination with zidovudine, results in a significant reduction in the risk of disease progression and mortality.

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.

Lamivudine has been widely used as a component of antiretroviral combination therapy with other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse transcriptase inhibitors).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.

The relationship between in vitro susceptibility of HIV to lamivudine and clinical response to lamivudine-containing therapy remains under investigation.

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of adult patients with chronic HBV infection (for details of clinical studies, see the prescribing information for Zeffix). However, for the treatment of HIV infection only a 300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.

Once daily dosing (300 mg once a day): a clinical study has demonstrated the non-inferiority between lamivudine once a day and lamivudine twice a day containing regimens. These results were obtained in an antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC stage A).

Tenofovir disoproxil

The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively.

In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir disoproxil 245 mg (as fumarate) for 24 weeks. The mean baseline CD4 cell count was 427 cells/mm3, the mean baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of < 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years. Baseline genotypic analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase inhibitors.

At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels (DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 245 mg (as fumarate) recipients (p < 0.0001). A statistically significant difference in favour of tenofovir disoproxil 245 mg (as fumarate) was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 count (+13 cells/mm3 for tenofovir disoproxil 245 mg (as fumarate) versus -11 cells/mm3 for placebo, p-value = 0.0008). The antiviral response to tenofovir disoproxil was durable through 48 weeks (DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg (as fumarate) treated patients developed the K65R mutation within the first 48 weeks.

The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy. The mean baseline CD4 cell count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of patients had symptomatic HIV-1 infection and 18% had AIDS. Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads > 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml.

By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 84% and 80% in the stavudine arm. At 144 weeks, the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 64% and 63% in the stavudine arm.

The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). At 144 weeks of treatment, the average change from baseline remained similar in both treatment groups (-3.07 and -3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). A consistent response to treatment with tenofovir disoproxil 245 mg (as fumarate) was seen regardless of baseline HIV-1 RNA and CD4 count.

The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil group than the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance either preceded or was coincident with the development of K65R in all cases. Eight patients had HIV that expressed K65R in the tenofovir disoproxil 245 mg (as fumarate) arm, 7 of these occurred during the first 48 weeks of treatment and the last one at week 96. No further K65R development was observed up to week 144. One patient in the tenofovir disoproxil (as fumarate) arm developed the K70E substitution in the virus. From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir.

Data pertaining to HBV

HBV antiviral activity in vitro

The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 μmol/l, with CC50 (50% cytotoxicity concentration) values > 100 μmol/l.

Resistance

No HBV mutations associated with tenofovir disoproxil resistance have been identified (see Clinical efficacy and safety). In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus.

Clinical efficacy and safety

The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is based on virological, biochemical and serological responses in adults with HBeAg positive and HBeAg negative chronic hepatitis B. Treated patients included those who were treatment-naïve, lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histological responses in compensated patients.

Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and GS-US-174-0103)

Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 4 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) patients negative for HBeAg and positive for HBeAb.

In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis). Treatment with tenofovir disoproxil 245 mg (as fumarate) was also associated with significantly greater proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg treatment. Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis) at week 48 (see Table 4 below).

In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 (see Table 4 below).

Table 4: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at week 48

Study 174-0102 (HBeAg negative)

Study 174-0103 (HBeAg positive)

Parameter

Tenofovir disoproxil 245 mg (as fumarate)

n = 250

Adefovir dipivoxil 10 mg

n = 125

Tenofovir disoproxil 245 mg (as fumarate)

n = 176

Adefovir dipivoxil 10 mg

n = 90

Complete response (%)a

71*

49

67*

12

Histology

Histological response (%)b

72

69

74

68

Median HBV DNA reduction from baselinec

(log10 copies/ml)

-4.7*

-4.0

-6.4*

-3.7

HBV DNA (%)

< 400 copies/ml (< 69 IU/ml)

93*

63

76*

13

ALT (%)

Normalised ALTd

76

77

68*

54

Serology (%)

HBeAg loss/seroconversion

n/a

n/a

22/21

18/18

HBsAg loss/seroconversion

0/0

0/0

3*/1

0/0

* p-value versus adefovir dipivoxil < 0.05.

a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.

b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.

c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of detection (LOD) of the assay.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

n/a = not applicable.

Tenofovir disoproxil was associated with significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and study GS-US-174-0103; 69%, 9%), respectively.

Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n = 51) and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT (n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV DNA suppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml.

Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103

In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks (either tenofovir disoproxil 245 mg (as fumarate) or adefovir dipivoxil 10 mg), patients rolled over with no interruption in treatment to open-label tenofovir disoproxil. In studies GS-US-174-0102 and GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively. At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses were maintained with continued tenofovir disoproxil treatment (see Tables 5 and 6 below).

Table 5: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 288 and 384 open-label treatment

Study 174-0102 (HBeAg negative)

Parametera

Tenofovir disoproxil 245 mg (as fumarate)

n = 250

Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate)

n = 125

Week

96b

144e

192g

240i

288l

384o

96c

144f

192h

240j

288m

384p

HBV DNA (%)

< 400 copies/ml (< 69 IU/ml)

90

87

84

83

80

74

89

88

87

84

84

76

ALT (%)

Normalised ALTd

72

73

67

70

68

64

68

70

77

76

74

69

Serology (%)

HBeAg loss/ seroconversion

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

 

n/a

HBsAg loss/ seroconversion

0/0

0/0

0/0

0/0

0/0

1/1n

0/0

0/0

0/0

0/0k

1/1n

1/1n

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.

b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.

c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.

f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.

g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.

h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.

i 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.

j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.

k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at the time of the data cut-off. However, the subject's HBsAg loss was ultimately confirmed at the subsequent visit.

l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.

m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.

n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF).

o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.

p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

n/a = not applicable.

Table 6: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 288 and 384 open-label treatment

Study 174-0103 (HBeAg positive)

Parametera

Tenofovir disoproxil 245 mg (as fumarate)

n = 176

Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate)

n = 90

Week

96b

144e

192h

240j

288m

384o

96c

144f

192i

240k

288n

384p

HBV DNA (%)

< 400 copies/ml (< 69 IU/ml)

76

72

68

64

61

56

74

71

72

66

65

61

ALT (%)

Normalised ALTd

60

55

56

46

47

47

65

61

59

56

57

56

Serology (%)

HBeAg loss/ seroconversion

 

26/ 23

 

29/ 23

 

34/ 25

 

38/ 30

 

37/ 25

 

30/ 20

 

24/ 20

 

33/ 26

 

36/ 30

 

38/ 31

 

40/ 31

 

35/ 24

HBsAg loss/ seroconversion

5/ 4

8/ 6g

11/ 8g

11/ 8l

12/ 8l

15/ 12l

6/ 5

8/ 7g

8/ 7g

10/ 10l

11/ 10l

13/ 11l

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.

b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.

c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.

f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.

g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT).

h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.

i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.

j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.

k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.

l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-TDF).

m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.

n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.

o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.

p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 7 below). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosis score of at least 2 points.

Table 7: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects at week 240 compared to baseline

Study 174-0102

(HBeAg negative)

Study 174-0103

(HBeAg positive)

Tenofovir disoproxil 245 mg (as fumarate)

n = 250c

Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate)

n = 125d

Tenofovir disoproxil 245 mg (as fumarate)

n = 176c

Adefovir dipivoxil 10 mg roll over to tenofovir disoproxil 245 mg (as fumarate)

n = 90d

Histological responsea,b (%)

88

[130/148]

85

[63/74]

90

[63/70]

92

[36/39]

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) by week 240. Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).

b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score.

c 48 weeks double-blind tenofovir disoproxil followed by up to 192 weeks open-label.

d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil.

Experience in patients with HIV co-infection and prior lamivudine experience

In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg (as fumarate) in adult patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir arm were 9.45 log10 copies/ml (n = 27). Treatment with tenofovir disoproxil 245 mg (as fumarate) was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74 log10 copies/ml (n = 18). In addition, 61% of patients had normal ALT at week 48.

Experience in patients with persistent viral replication (study GS-US-174-0106)

The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) or tenofovir disoproxil 245 mg (as fumarate) plus 200 mg emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in HBeAg positive and HBeAg negative adult patients who had persistent viraemia (HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks. At baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine. Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine plus tenofovir disoproxil (p = 0.672). In addition 55% (29/53) of patients treated with tenofovir disoproxil had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus tenofovir disoproxil (p = 0.504). Comparisons between treatment groups beyond week 24 are difficult to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus tenofovir disoproxil. Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine plus tenofovir disoproxil in HBV monoinfected patients are ongoing.

Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108)

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety and efficacy of tenofovir disoproxil (n = 45), emtricitabine plus tenofovir disoproxil (n = 45), and entecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxil treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline. The co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl.

In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA < 400 copies/ml after 48 weeks of treatment.

Overall, the data derived from this study are too limited to draw any definitive conclusions on the comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 8 below).

Table 8: Safety and efficacy parameters in decompensated patients at week 48

Study 174-0108

Parameter

Tenofovir disoproxil 245 mg (as fumarate)

(n = 45)

Emtricitabine 200 mg/ tenofovir disoproxil 245 mg (as fumarate)

(n = 45)

Entecavir

(0.5 mg or 1 mg)

n = 22

Tolerability failure (permanent discontinuation of study drug due to a treatment emergent AE)

n (%)a

3 (7%)

2 (4%)

2 (9%)

Confirmed increase in serum creatinine ≥ 0.5 mg/dl from baseline or confirmed serum phosphate of < 2 mg/dl

n (%)b

4 (9%)

3 (7%)

1 (5%)

HBV DNA n (%) < 400 copies/ml

n (%)

31/44 (70%)

36/41 (88%)

16/22 (73%)

ALT n (%)

Normal ALT

25/44 (57%)

31/41 (76%)

12/22 (55%)

≥ 2 point decrease in CPT from baseline

n (%)

7/27 (26%)

12/25 (48%)

5/12 (42%)

Mean change from baseline in CPT score

-0.8

-0.9

-1.3

Mean change from baseline in MELD score

-1.8

-2.3

-2.6

a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622,

b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000.

Experience beyond 48 weeks in study GS-US-174-0108

Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168.

Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121)

The efficacy and safety of 245 mg tenofovir disoproxil (as fumarate) was evaluated in a randomised, double-blind study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). Only five had adefovir-associated resistance mutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovir disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively. Baseline demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and mean ALT was 79 U/l, respectively.

After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had HBV DNA < 400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation. After 240 weeks of treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation. Among the HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects (19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion through week 240. Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by Week 240, but not seroconversion to anti-HBs. Five subjects randomised to emtricitabine plus tenofovir disoproxil experienced HBsAg loss, with 2 of these 5 subjects experiencing seroconversion to anti-HBs.

Clinical resistance

Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive (GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovir disoproxil resistance have developed.

Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive (GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and 384 (n = 2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovir disoproxil resistance have developed.

In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA > 400 copies/ml at week 48. No amino acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. Genotypic analysis was conducted for 5 subjects in the tenofovir disoproxil arm post week 48. No amino acid substitutions associated with tenofovir disoproxil resistance were detected in any subject.

In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received tenofovir disoproxil for up to 240 weeks. Cumulatively, there were 4 patients who experienced a viremic episode (HBV DNA>400 copies/ml) at their last timepoint on TDF. Among them, sequence data from paired baseline and on treatment HBV isolates were available for 2 of 4 patients. No amino acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates.

5.2 Pharmacokinetic properties

Absorption

Lamivudine

Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time (tmax) to maximal serum concentrations (Cmax) is about an hour. Based on data derived from a study in healthy volunteers, at a therapeutic dose of 150 mg twice daily, mean (CV) steady-state Cmax and Cmin of lamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml (27%), respectively. The mean (CV) AUC over a dosing interval of 12 hours is 4.7 µg.h/ml (18%). At a therapeutic dose of 300mg once daily, the mean (CV) steady-state Cmax, Cmin and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and 8.9 µg.h/ml (21%), respectively.

The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC, Cmax, and tmax.

Co-administration of lamivudine with food results in a delay of tmax and a lower Cmax (decreased by 47%). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.

Co-administration of zidovudine results in a 13 % increase in zidovudine exposure and a 28 % increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.

Tenofovir disoproxil

Following oral administration of tenofovir disoproxil to HIV infected patients, tenofovir disoproxil is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted patients was approximately 25%. Administration of tenofovir disoproxil with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of tenofovir disoproxil in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil with a light meal did not have a significant effect on the pharmacokinetics of tenofovir.

Distribution

Lamivudine

From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system.

Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 16% - 36% to serum albumin in in vitro studies).

Limited data show that lamivudine penetrates the central nervous system and reaches the cerebro-spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral administration was approximately 0.12. The true extent of penetration or relationship with any clinical efficacy is unknown.

Tenofovir disoproxil

Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/ml.

Biotransformation

Lamivudine

The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60 healthy adult volunteers, lamivudine 300 mg once daily has been demonstrated to be pharmacokinetically equivalent at steady-state to lamivudine 150 mg twice daily with respect to intracellular triphosphate AUC24 and Cmax.

Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions of lamivudine with other medicinal products is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding.

Tenofovir disoproxil

In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil at a concentration of 100 µmol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil and medicinal products metabolised by CYP450 would occur.

Elimination

Lamivudine

Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below 50 ml/min is shown in the dosage section.

An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment (see sections 4.5). Administration of co-trimoxazole with lamivudine in patients with renal impairment should be carefully assessed.

Tenofovir disoproxil

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration the terminal half-life of tenofovir is approximately 12 to 18 hours.

Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4).

Pharmacokinetics in pregnancy

Lamivudine

Following oral administration, lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant women.

Tenofovir disoproxil

Linearity/non-linearity

The pharmacokinetics of tenofovir were independent of tenofovir disoproxil dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level.

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.

Renal impairment

Lamivudine and tenofovir disoproxil tablet is not recommended for use in patients with a creatinine clearance < 50 ml/min, as appropriate dose adjustments are not possible.

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to respectively 3,064 (30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with mild, moderate and severe renal impairment. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown.

In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml and a mean AUC0-48h of 42,857 ng·h/ml.

It is recommended that the dosing interval for tenofovir disoproxil 245 mg (as fumarate) is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis.

The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.

The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections 4.2 and 4.4).

Hepatic impairment

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng/ml and 2,050 (50.8%) ng·h/ml, respectively, in normal subjects compared with 289 (46.0%) ng/ml and 2,310 (43.5%) ng·h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/ml and 2,740 (44.0%) ng·h/ml in subjects with severe hepatic impairment.

Intracellular pharmacokinetics

In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.

5.3 Preclinical safety data

Lamivudine

Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.

Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivo at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.

A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero to the combination sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.

The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans.

A fertility study in rats has shown that lamivudine had no effect on male or female fertility.

Tenofovir disoproxil

Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in 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.

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 reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.

The active substance tenofovir disoproxil and its main transformation products are persistent in the environment.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Microcrystalline cellulose (E460),

Croscarmellose sodium (E468),

Starch pregelatinized Ph.Eur (Maize Starch 1500),

Magnesium stearate (E572).

Tablet film-coat

Hypromellose 6cps (E464),

Opadry II 85G18490 white containing polyvinyl alcohol- part hydrolyzed (E1203), titanium dioxide (E171), talc (E553b), macrogol 4000 (E1521), lecithin (soya) (E322).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Blister: This medicinal product does not require any special temperature storage conditions

HDPE bottles: This medicinal product does not require any special temperature storage conditions. Store in the original bottle in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

HDPE container of 30 tablets composed of 50 cc white HDPE container with 38 mm white PP child resistant cap and 1 gm Silica gel bag and bundled pack of 3 bottles of 30 tablets

Blister pack of 10 tablets composed of 3 ply Alu-Alu film and aluminium blister foil and box of 30 tablets and bundled pack of 3 boxes of 30 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal

7. Marketing authorisation holder

Cipla (EU) Limited

Dixcart House,Addlestone Road,

Bourne Business Park Addlestone

KT15 2LE

United Kingdom.

8. Marketing authorisation number(s)

PL 36390/0217

9. Date of first authorisation/renewal of the authorisation

27/10/2017

10. Date of revision of the text

18/01/2019