lamivudine: prescribing information – dosing, contraindications, interactions, side effects

Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

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

Epivir may be administered with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.

Epivir is also available as an oral solution for children over three months of age and who weigh less than 14 kg or for patients who are unable to swallow tablets (see section 4.4).
Patients changing between lamivudine oral solution and lamivudine tablets should follow the dosing recommendations that are specific for the formulation (see section 5.2)

Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

Adults, adolescents and children (weighing at least 25 kg):

The recommended dose of Epivir is 300 mg daily. This may be administered as either 150 mg twice daily or 300 mg once daily (see section 4.4).

The 300 mg tablet is only suitable for the once a day regimen.

Children (weighing less than 25 kg):

Dosing according to weight bands is recommended for Epivir tablets.

Children weighing ≥ 20 kg to < 25 kg: The recommended dose is 225 mg daily. This may be administered as either 75 mg (one-half of a 150 mg tablet) taken in the morning and 150 mg (one whole 150 mg tablet) taken in the evening, or 225 mg (one and a half 150 mg tablets) taken once daily.

Children weighing 14 to < 20 kg: The recommended dose is 150 mg daily. This may be administered as 75 mg (one-half of a 150 mg tablet) taken twice daily, or 150 mg (one whole 150 mg tablet) taken once daily.

Children from three months of age: As an accurate dosage cannot be achieved with the 300 mg non- scored tablet formulation in this patient population, it is recommended that the Epivir 150 mg scored tablet formulation is used and the corresponding recommended dosage instructions are followed.

Children less than three months of age: The limited data available are insufficient to propose specific dosage recommendations (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take the recommended once daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the recommended once daily dose (as described above) approximately every 24 hours. When changing back to a twice daily regimen, patients should take the recommended twice daily dose approximately 24 hours after the last once daily dose.

Special populations:

Older people: No specific data are available; however, special care is advised in this age group due to age-associated changes such as the decrease in renal function and alteration of haematological parameters.

Renal impairment: Lamivudine concentrations are increased in patients with moderate - severe renal impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution presentation of Epivir for patients whose creatinine clearance falls below 30 mL/min (see tables).

Dosing recommendations – Adults, adolescents and children (weighing at least 25 kg):

Creatinine clearance
(mL/min)
First dose
Maintenance dose
 50
300 mg or
150 mg
300 mg once daily or
150 mg twice daily
30 - < 50
150 mg
150 mg once daily
<30 As doses below 150 mg are needed the use of the oral solution is recommended

15 to < 30
150 mg
100 mg once daily
5 to < 15
150 mg
50 mg once daily

< 5
50 mg
25 mg once daily

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in adults, it is recommended that the dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults. The Epivir 10 mg/mL oral solution may be the most appropriate formulation to achieve the recommended dose in children with renal impairment aged at least 3 months and weighing less than 25 kg.

Dosing recommendations – Children aged at least 3 months and weighing less than 25 kg:

Creatinine clearance
(mL/min)
First dose
Maintenance dose
 50
10 mg/kg or
5 mg/kg
10 mg/kg once daily or
5 mg/kg twice daily
30 to< 50
5 mg/kg
5 mg/kg once daily
15 to < 30
5 mg/kg
3.3 mg/kg once daily
5 to < 15
5 mg/kg
1.6 mg/kg once daily
< 5
1.6 mg/kg
0.9 mg/kg once daily

Hepatic impairment: Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

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

Epivir may be administered with or without food.

Epivir is also available as a tablet formulation for patients who weigh at least 14 kg (see section 4.4).

Patients changing between lamivudine tablets and lamivudine oral solution should follow the dosing recommendations that are specific for the formulation (see section 5.2).

For patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

Adults, adolescents and children (weighing at least 25 kg):

The recommended dose of Epivir is 300 mg daily. This may be administered as either 150 mg (15 mL) twice daily or 300 mg (30 mL) once daily (see section 4.4).

Children (weighing less than 25 kg):

Children from one year of age: The recommended dose is 0.5 mL/kg (5 mg/kg) twice daily, or 1 mL/kg (10 mg/kg) once daily (see sections 4.4 and 4.5).

Children from three months to one year of age: The recommended dose is 0.5 mL/kg (5 mg/kg) twice daily. If a twice daily regimen is not feasible, a once daily regimen (10 mg/kg/day) could be considered. It should be taken into account that data for the once daily regimen are very limited in this population (see sections 4.4, 5.1 and 5.2).

Children less than three months of age: The limited data available are insufficient to propose specific dosage recommendations (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take the recommended once daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the recommended once daily dose (as described above) approximately every 24 hours. When changing back to a twice daily regimen, patients should take the recommended twice daily dose approximately 24 hours after the last once daily dose.

Special populations:

Older people: No specific data are available; however, special care is advised in this age group due to age-associated changes such as the decrease in renal function and alteration of haematological parameters.

Renal impairment: Lamivudine concentrations are increased in patients with moderate - severe renal impairment due to decreased clearance. The dose should therefore be adjusted (see tables).

Dosing recommendations – Adults, adolescents and children (weighing at least 25 kg):

Creatinine clearance
(mL/min)

First dose
Maintenance dose
50
300 mg (30 mL) or
150 mg (15 mL)
300 mg (30 mL) once daily or
150 mg (15 mL) twice daily
30 to<50
150 mg (15 mL)
150 mg (15 mL) once daily
15 to <30
150 mg (15 mL)
100 mg (10 mL) once daily
5 to <15
150 mg (15 mL)
50 mg (5 mL) once daily
<5
50 mg (5 mL)
25 mg (2.5 mL) once daily

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in adults; it is recommended that the dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults. The Epivir 10 mg/mL oral solution may be the most appropriate formulation to achieve the recommended dose in children with renal impairment aged at least 3 months and weighing less than 25kg.

Dosing recommendations – Children aged at least 3 months and weighing less than 25 kg:

Creatinine clearance
(mL/min)
First dose
Maintenance dose
50
10 mg/kg or
5 mg/kg
10 mg/kg once daily or
5 mg/kg twice daily
30 to<50
5 mg/kg
5 mg/kg once daily
15 to <30
5 mg/kg
3.3 mg/kg once daily
5 to <15
5 mg/kg
1.6 mg/kg once daily
<5
1.6 mg/kg
0.9 mg/kg once daily

Hepatic impairment: Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

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

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

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.

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

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 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 (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).

Paediatric population

1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW study (COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 5.1). No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.

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.

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

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.

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

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 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 (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).

Paediatric population

1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 5.1). No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.

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.

Epivir is not recommended for use as monotherapy.

Renal impairment

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).

Triple nucleoside therapy

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

Opportunistic infections

Patients receiving Epivir 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 Epivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide 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 nucleoside and nucleotide analogues, who presents 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 jirovecii pneumonia (often referred to as PCP). 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.

Liver disease

If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SPC.

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. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see Zeffix SPC).

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).

Paediatric population

In a study performed in paediatric patients (see section 5.1 ARROW study), lower rates of virologic suppression and more frequent viral resistance were reported in children receiving the oral solution of Epivir as compared to those receiving the tablet formulation. Whenever possible in children, Epivir as tablet formulation should preferably be used.

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.

Drug Interactions

Epivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine (see section 4.5).

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

Excipients

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

Epivir is not recommended for use as monotherapy.

Renal impairment

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).

Triple nucleoside therapy

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

Opportunistic infections

Patients receiving Epivir 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 Epivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide 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 postnatally 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 nucleoside and nucleotide analogues, who presents 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 jirovecii pneumonia (often referred to as PCP). 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.

Liver disease

If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SPC.

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. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see Zeffix SPC).

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).

Excipients

Contains 3 g of sucrose in each dose (150 mg = 15 mL). This should be taken into account in patients with diabetes mellitus.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. Sucrose may be harmful to the teeth.

This medicinal product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. These may cause allergic reactions (possibly delayed).

This medicinal product contains 300 mg propylene glycol in each 15 mL.

This medicinal product contains 39 mg sodium per 15 mL, equivalent to 1.95% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric Population

In a study performed in paediatric patients (see section 5.1 ARROW study), lower rates of virologic suppression and more frequent viral resistance were reported in children receiving the oral solution of Epivir as compared to those receiving the tablet formulation.

Whenever possible in children, an all-tablet regimen should preferably be used. Epivir oral solution given concomitantly with sorbitol-containing medicines should be used only when an all-tablet regimen cannot be used and the benefits of treatment outweigh possible risks including lower virological suppression. Consider more frequent monitoring of HIV-1 viral load when Epivir is used with chronically-administered, sorbitol-containing medicines [e.g. Ziagen oral solution]. Although not studied, the same effect would be expected with other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol (see section 4.5)).

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.

Drug Interactions

Epivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine (see section 4.5).

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

Interaction studies have only been performed in adults.

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 (see section 4.2). 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 jirovecii 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).

Due to similarities, Epivir should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other medicinal products containing lamivudine (see section 4.4).

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.

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of Epivir with medicinal products containing sorbitol or other osmotic acting poly- alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Interaction studies have only been performed in adults.

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 (see section 4.2). 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 jirovecii 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).

Due to similarities, Epivir should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other medicinal products containing lamivudine (see section 4.4).

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.

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of Epivir with medicinal products containing sorbitol or other osmotic acting poly- alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided (see section 4.4).

Pregnancy

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 evidence of malformative or foeto/neonatal toxicity of Epivir. Epivir can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on those data.

For patients co-infected with hepatitis who are being treated with lamivudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

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 postnatally to nucleoside analogues (see section 4.4).

Breast-feeding

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. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

Fertility

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

Epivir has no or negligible influence on the ability to drive and use machines. However, patients should be informed that malaise and fatigue have been reported during treatment with lamivudine (see section 4.8). The clinical status of the patient and the adverse reaction profile of

lamivudine should be borne in mind when considering the patient's ability to drive or operate machinery.

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. No specific signs or symptoms have been identified following acute overdose with lamivudine, apart from those listed as undesirable effects.

If overdosage occurs the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.

Mechanism of action

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).

Resistance

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.

Clinical efficacy and safety

Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.

Mechanism of action

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).

Resistance

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.

Clinical efficacy and safety

Absorption

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 300 mg 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. Administration of Epivir tablets is bioequivalent to Epivir oral solution with respect to AUC∞ and Cmax in adults. Absorption differences have been observed between adult and paediatric populations (see Special populations).

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

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

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.

Distribution

Absorption

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 300 mg 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.

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

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

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.

Distribution

From intravenous studies, the mean volume of distribution is 1.3 l/kg. 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).

Zeffix is indicated for the treatment of chronic hepatitis B in adults with:

▪ compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see section 5.1).

▪ decompensated liver disease in combination with a second agent without cross-resistance to lamivudine (see section 4.2).

Zeffix is indicated for the treatment of chronic hepatitis B in adults with:

▪ compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see section 5.1).

▪ decompensated liver disease in combination with a second agent, without cross-resistance to lamivudine (see section 4.2).

Therapy with Zeffix should be initiated by a physician experienced in the management of chronic hepatitis B.

Posology

Adults
The recommended dosage of Zeffix is 100 mg once daily.

In patients with decompensated liver disease, lamivudine should always be used in combination with a second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve rapid viral suppression.

Duration of treatment
The optimal duration of treatment is unknown.

• In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should be administered for at least 6-12 months after HBeAg seroconversion (HBeAg and HBV DNA loss with HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAg seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels

should be followed regularly after treatment discontinuation to detect any late virological relapse.
- In patients with HBeAg negative CHB (pre-core mutant) without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment, regular reassessment is recommended to confirm that continuation of the selected therapy remains appropriate for the patient.
- In patients with decompensated liver disease or cirrhosis and in liver transplant recipients, treatment cessation is not recommended (see section 5.1).

If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis (see section 4.4).

Clinical resistance
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD (tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic response to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In order to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition of an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines should be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment (see section 5.1).

Special populations

Renal impairment
Lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renal impairment due to decreased renal clearance. The dosage should, therefore, be reduced for patients with a creatinine clearance of < 50 ml/minute. When doses below 100 mg are required Zeffix oral solution should be used (see Table 1 below).

Table 1: Dosage of Zeffix in patients with decreased renal clearance.

Creatinine clearance ml/min

First dose of Zeffix oral solution*

Maintenance dose once daily

30 to < 50

20 ml (100 mg)

10 ml (50 mg)

15 to < 30

20 ml (100 mg)

5 ml (25 mg)

5 to < 15

7 ml (35 mg)

3 ml (15 mg)

< 5

7 ml (35 mg)

2 ml (10 mg)
* Zeffix oral solution containing 5 mg/ml lamivudine.

Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hours dialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correct for the patient’s creatinine clearance, no further dosage adjustments are required while undergoing dialysis.

Hepatic impairment
Data obtained in patients with hepatic impairment, including those with end-stage liver disease awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment unless accompanied by renal impairment.

HIV co-infection
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to receive combined antiretroviral treatment including lamivudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be used.

Elderly
In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min.

Paediatric population
The safety and efficacy of Zeffix in infants, children and adolescents aged below 18 years have not been established. Currently available data are described in sections 4.4 and 5.1 but no recommendation on a posology can be made.

Method of administration

Oral use.
Zeffix can be taken with or without food.

Therapy with Zeffix should be initiated by a physician experienced in the management of chronic hepatitis B.

Posology

Adults
The recommended dosage of Zeffix is 100 mg once daily.

In patients with decompensated liver disease, lamivudine should always be used in combination with a second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve rapid viral suppression.

Duration of treatment
The optimal duration of treatment is unknown.

• In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should be administered for at least 6-12 months after HBeAg seroconversion (HBeAg and HBV DNA loss with HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAg seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
• In patients with HBeAg negative CHB (pre-core mutant), without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment, regular reassessment is recommended to confirm that continuation of the selected therapy remains appropriate for the patient.
• In patients with decompensated liver disease or cirrhosis and in liver transplant recipients, treatment cessation is not recommended (see section 5.1).

If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis (see section 4.4).

Clinical resistance
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD (tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic response to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In order to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition of an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines should be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment (see section 5.1).

Special populations

Renal impairment
Lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renal impairment due to decreased renal clearance. The dosage should, therefore, be reduced for patients with a creatinine clearance of < 50 ml/minute. When doses below 100 mg are required Zeffix oral solution should be used (see Table 1 below).

Table 1: Dosage of Zeffix in patients with decreased renal clearance.

Creatinine clearance ml/min

First dose of Zeffix oral solution

Maintenance dose once daily

30 to < 50

20 ml (100 mg)

10 ml (50 mg)

15 to < 30

20 ml (100 mg)

5 ml (25 mg)

5 to < 15

7 ml (35 mg)

3 ml (15 mg)

< 5

7 ml (35 mg)

2 ml (10 mg)

Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hours dialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correct for the patient’s creatinine clearance, no further dosage adjustments are required while undergoing dialysis.

Hepatic impairment
Data obtained in patients with hepatic impairment, including those with end-stage liver disease awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment unless accompanied by renal impairment.

HIV co-infection
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to receive combined antiretroviral treatment including lamivudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be used.

Elderly
In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min.

Paediatric population
The safety and efficacy of Zeffix in infants, children and adolescents aged below 18 years have not been established. Currently available data are described in sections 4.4 and 5.1 but no recommendation on a posology can be made.

Method of administration

Oral use.
Zeffix can be taken with or without food.

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

Summary of the safety profile

The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine treated patients. The most common adverse reactions reported were malaise and fatigue, respiratory tract infections, throat and tonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea.

Tabulated list of adverse reactions

Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. 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) and not known (cannot be estimated from the available data).

The frequency categories assigned to the adverse reactions are mainly based on experience from clinical trials including a total of 1 171 patients with chronic hepatitis B receiving lamivudine at 100 mg.

Blood and lymphatic system disorders
Not known
Thrombocytopenia
Metabolism and nutrition disorders
Very rare
Lactic acidosis
Immune system disorders
Rare
Angioedema
Hepatobiliary disorders
Very common
ALT elevations (see section 4.4)
Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported ‘on-treatment’ and following lamivudine withdrawal. Most events have been self-limited, however fatalities have been observed very rarely (see section 4.4).
Skin and subcutaneous tissue disorders
Common
Rash, pruritus
Musculoskeletal and connective tissue disorders
Common
Elevations of CPK
Common
Muscle disorders, including myalgia and cramps*
Not known
Rhabdomyolysis
* In Phase III studies frequency observed in the lamivudine treatment group was not greater than observed in the placebo group

Paediatric population

Based on limited data in children aged 2 to 17 years, there were no new safety issues identified compared to adults.

Other special populations

In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paraesthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and lamivudine treated patients.

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.

Exacerbations of hepatitis

Exacerbations 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 as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation.

HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been identified with extended therapy. In some patients the development of YMDD mutant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross resistance to lamivudine based on therapeutic guidelines should be considered (see section 5.1).

Exacerbations after treatment discontinuation
Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21 %) compared with those receiving placebo (8 %). However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some fatalities have been observed. If Zeffix is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months, and then as clinically indicated.

Exacerbations in patients with decompensated cirrhosis
Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at

discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. These patients should be monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function, and antiviral response during treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months after treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored more frequently as appropriate.

For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of lamivudine treatment.

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. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour).
The neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in cases which have relevant signs or symptoms.

Paediatric population

Lamivudine has been administered to children (2 years and above) and adolescents with compensated chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this patient population is not currently recommended (see section 5.1).

Delta hepatitis or hepatitis C

The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been established and caution is advised.

Immunosuppressive treatments

Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those receiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine should be used with caution in these patients.

Monitoring

During treatment with Zeffix patients should be monitored regularly. Serum ALT and HBV DNA levels should be monitored at 3-month intervals and in HBeAg positive patients HBeAg should be assessed every 6 months.

HIV co-infection

For the treatment of patients who are co-infected with HIV and are currently receiving or plan to receive treatment with an antiretroviral combination regimen including lamivudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be used.

The 100 mg usual dose of lamivudine used for the treatment of HBV is not appropriate for patients who acquire HIV or are co-infected with HBV and HIV. If a patient with unrecognised or untreated HIV infection is prescribed the dose of lamivudine recommended for the treatment of HBV, rapid emergence of HIV resistance and a limitation of treatment options is likely to result because of the

subtherapeutic dose and the inappropriate use of monotherapy for HIV treatment. HIV counselling and testing should be offered to all patients before beginning treatment with lamivudine for HBV and periodically during treatment.

Transmission of hepatitis B

There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B virus immunisation in infants should be followed.

Patients should be advised that therapy with lamivudine has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken.

Interactions with other medicinal products

Zeffix should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine (see section 4.5).

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

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Exacerbations of hepatitis

Exacerbations 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 as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation.

HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been identified with extended therapy. In some patients the development of YMDD mutant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross-resistance to lamivudine based on therapeutic guideline should be considered (see section 5.1).

Exacerbations after treatment discontinuation
Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21 %) compared with those receiving placebo (8 %). However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some fatalities have been observed. If Zeffix is discontinued, patients should be periodically monitored both

clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months, and then as clinically indicated.

Exacerbations in patients with decompensated cirrhosis
Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. These patients should be monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function, and antiviral response during treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months after treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored more frequently as appropriate.

For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of lamivudine treatment.

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. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour).
The neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in cases which have relevant signs or symptoms.

Paediatric population

Lamivudine has been administered to children (2 years and above) and adolescents with compensated chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this patient population is not currently recommended (see section 5.1).

Delta hepatitis or hepatitis C

The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been established and caution is advised.

Immunosuppressive treatments

Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those receiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine should be used with caution in these patients.

Monitoring

During treatment with Zeffix patients should be monitored regularly. Serum ALT and HBV DNA levels should be monitored at 3-month intervals and in HBeAg positive patients HBeAg should be assessed every 6 months.

HIV co-infection

For the treatment of patients who are co-infected with HIV and are currently receiving or plan to receive treatment with an antiretroviral combination regimen including lamivudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other

antiretrovirals) should be used.

The 100 mg usual dose of lamivudine used for the treatment of HBV is not appropriate for patients who acquire HIV or are co-infected with HBV and HIV. If a patient with unrecognised or untreated HIV infection is prescribed the dose of lamivudine recommended for the treatment of HBV, rapid emergence of HIV resistance and a limitation of treatment options is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV treatment. HIV counselling and testing should be offered to all patients before beginning treatment with lamivudine for HBV and periodically during treatment.

Transmission of hepatitis B

There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B virus immunisation in infants should be followed.

Patients should be advised that therapy with lamivudine has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken.

Interactions with other medicinal products

Zeffix should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine (see section 4.5).

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

Excipients

Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. Sucrose may be harmful to the teeth. Diabetic patients should be advised that each dose of oral solution (100 mg = 20 ml) contains 4 g of sucrose.

Propyl parahydroxybenzoate and methyl parahydroxybenzoate
The oral solution contains propyl and methyl parahydroxybenzoates. These preservatives may cause allergic reactions (possibly delayed).

Propylene glycol
This medicinal product contains 400 mg propylene glycol in each 20 ml.

Sodium
This medicinal product contains 58.8 mg sodium per 20 ml, equivalent to 2.9 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Interaction studies have only been performed in adults.

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

Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their 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.

Substances shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.

Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary.

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

Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinal products are concurrently administered. There were no observed clinically significant adverse interactions in patients taking lamivudine concurrently with commonly used immunosuppressant medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been performed.

Emtricitabine

Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Zeffix should not be taken with any other medicinal products containing lamivudine (see section 4.4).

Cladribine

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).

Sorbitol

Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose (adult HIV daily dose) of lamivudine oral solution resulted in dose-dependent decreases of 14 %, 32 %, and 36 % in lamivudine exposure (AUC) and 28 %, 52 %, and 55 % in the Cmax of lamivudine in adults. When possible, avoid chronic co-administration of Zeffix with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HBV viral load when chronic co-administration cannot be avoided.

Pregnancy

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.

Available human data from the Antiretroviral Pregnancy Registry reporting more than 1 000 outcomes from first trimester and more than 1 000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/ neonatal effect. Less than 1 % of these women have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other concomitant medications. Zeffix can be used during pregnancy if clinically needed.

For patients who are being treated with lamivudine and subsequently become pregnant consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Breast-feeding

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 (less than 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and is therefore likely to result in exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B is not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk leads to adverse reactions in breastfed infants. Therefore, breastfeeding may be considered in breast-feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce the risk of the emergence of lamivudine resistant mutants in the infant.

Fertility

Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3).

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).

Pregnancy

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.

Available human data from the Antiretroviral Pregnancy Registry reporting more than 1 000 outcomes from first trimester and more than 1 000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Less than 1 % of these women have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other concomitant medications. Zeffix can be used during pregnancy if clinically needed.

For patients who are being treated with lamivudine and subsequently become pregnant consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Breast-feeding

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 (less than 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and is therefore likely to result in exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B is not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk leads to adverse reactions in breastfed infants. Therefore, breastfeeding may be considered in breast-feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce the risk of the emergence of lamivudine resistant mutants in the infant.

Fertility

Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3).

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).

Patients should be informed that malaise and fatigue have been reported during treatment with lamivudine. The clinical status of the patient and the adverse reaction profile of lamivudine should be borne in mind when considering the patient's ability to drive or operate machinery.

No specific signs or symptoms have been identified following acute overdose with lamivudine, apart from those listed as adverse reactions.

If overdose occurs the patient should be monitored and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.

5.
PHARMACOLOGICAL PROPERTIES

No specific signs or symptoms have been identified following acute overdose with lamivudine, apart from those listed as adverse reactions.

If overdose occurs the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF05.

Mechanism of action

Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in experimentally infected animals.

Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase.

The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.

Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.

In assays relating to potential substance effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.

Clinical efficacy and safety

Experience in patients with HBeAg positive CHB and compensated liver disease
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication [34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridization assay, LLOD < 1.6 pg/ml)], normalised ALT level (40-72 % of patients), induced HBeAg seroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay], 16-18 % of patients), improved histology (38-52 % of patients had a  2 point decrease in the Knodell Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) and progression to cirrhosis.

Continued lamivudine treatment for an additional 2 years in patients who had failed to achieve HBeAg seroconversion in the initial 1-year controlled studies resulted in further improvement in bridging fibrosis. In patients with YMDD mutant HBV, 41/82 (50 %) patients had improvement in liver inflammation and 40/56 (71 %) patients without YMDD mutant HBV had improvement. Improvement in bridging fibrosis occurred in 19/30 (63 %) patients without YMDD mutant and 22/44 (50 %) patients with the mutant. Five percent (3/56) of patients without the YMDD mutant and 13 % (11/82) of patients with YMDD mutant showed worsening in liver inflammation compared to pre-treatment.
Progression to cirrhosis occurred in 4/68 (6 %) patients with the YMDD mutant, whereas no patients without the mutant progressed to cirrhosis.

Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF05

Mechanism of action

Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in experimentally infected animals.

Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase.

The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.

Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.

In assays relating to potential substance effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.

Clinical efficacy and safety

Experience in patients with HBeAg positive CHB and compensated liver disease
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication (34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridization assay, LLOD < 1.6 pg/ml)], normalised ALT level (40-72 % of patients), induced HBeAg seroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay], 16-18 % of patients), improved histology (38-52 % of patients had a  2 point decrease in the Knodell Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) and progression to cirrhosis.

Continued lamivudine treatment for an additional 2 years in patients who had failed to achieve HBeAg seroconversion in the initial 1-year controlled studies resulted in further improvement in bridging fibrosis. In patients with YMDD mutant HBV, 41/82 (50 %) patients had improvement in liver inflammation and 40/56 (71 %) patients without YMDD mutant HBV had improvement. Improvement in bridging fibrosis occurred in 19/30 (63 %) patients without YMDD mutant and 22/44 (50 %) patients with the mutant. Five percent (3/56) of patients without the YMDD mutant and 13 % (11/82) of patients with YMDD mutant showed worsening in liver inflammation compared to pre-treatment.
Progression to cirrhosis occurred in 4/68 (6 %) patients with the YMDD mutant, whereas no patients without the mutant progressed to cirrhosis.

Absorption

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. At therapeutic dose levels i.e.

100 mg once daily, Cmax is in the order of 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml.

Co-administration of lamivudine with food resulted in a delay of Tmax and a lower Cmax (decreased by up to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore lamivudine can be administered with or without food.

Distribution

From intravenous studies the mean volume of distribution is 1.3 l/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin.
Limited data shows lamivudine penetrates the central nervous system and reaches the cerebro-spinal fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administration was approximately 0.12.

Biotransformation

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

Elimination

The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life of elimination is 18 to 19 hours. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts for about 70 % of lamivudine elimination.

Special populations

Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of < 50 ml/min is necessary (see section 4.2).

Absorption

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. At therapeutic dose levels i.e., 100 mg once daily, Cmax is in the order of 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml.

Co-administration of lamivudine with food resulted in a delay of Tmax and a lower Cmax (decreased by up to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore lamivudine can be administered with or without food.

Distribution

From intravenous studies the mean volume of distribution is 1.3 l/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin.

Limited data shows lamivudine penetrates the central nervous system and reaches the cerebro-spinal fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administration was approximately 0.12.

Biotransformation

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

Elimination

The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life of elimination is 18 to 19 hours. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts for about 70 % of lamivudine elimination.

Special populations

Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of < 50 ml/min is necessary (see section 4.2).