4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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 hrs 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.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 patients

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 medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. 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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), 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 100mg.

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 paresthesia) 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.