Active ingredients: Lamivudine
Zeffix 5 mg / ml oral solution
Zeffix package inserts are available for pack sizes:- Zeffix 100 mg film-coated tablets
- Zeffix 5 mg / ml oral solution
Why is Zeffix used? What is it for?
The active ingredient contained in Zeffix is lamivudine.
Zeffix is used to treat chronic (long-lasting) hepatitis B infection in adults.
Zeffix is an antiviral medicine that suppresses the hepatitis B virus and belongs to a group of medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs).
Hepatitis B is caused by a virus that infects the liver, causes a chronic (long-lasting) infection, and can damage the liver. Zeffix can be used in people whose liver is damaged but still functions normally (compensated liver disease) and in combination with other medicines in people whose liver is damaged and does not function normally (decompensated liver disease).
Treatment with Zeffix can reduce the amount of hepatitis B virus in the body. This should lead to a reduction in liver damage and an improvement in liver function. Not all people respond to treatment with Zeffix in the same way. Your doctor will check the effectiveness of the treatment with regular blood tests.
Contraindications When Zeffix should not be used
Do not take Zeffix
- if you are allergic to lamivudine or any of the other ingredients of this medicine
- Talk to your doctor if you think this applies to you.
Precautions for use What you need to know before taking Zeffix
Some people taking Zeffix or other similar medicines are at increased risk of serious side effects. You need to be aware of these additional risks:
- if you have had other types of liver disease such as hepatitis C
- if you are severely overweight (especially if you are a woman).
- Tell your doctor if any of these apply to you. You may need further checks, including blood tests, while you are taking the medicine.
Do not stop taking Zeffix without your doctor's advice, as there is a risk of your hepatitis getting worse. If you stop taking Zeffix, your doctor will monitor you for at least four months to check for any problems. This will involve taking blood samples to check for any increases in liver enzyme levels, which may indicate liver damage. See section 3 for more information on how to take Zeffix.
Protection of other people
Hepatitis B infection is spread through sexual intercourse with people who have the infection or through the transfer of infected blood (for example, through the exchange of injection needles). Zeffix will not prevent transmission of hepatitis B infection to other people. To protect other people from hepatitis B infection:
- use a condom for oral or penetrative sex.
- do not risk contact with blood - for example, do not exchange needles.
Interactions Which drugs or foods may change the effect of Zeffix
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including herbal medicines or other medicines bought without a prescription.
Remember to tell your doctor or pharmacist if you are taking any new medicine while taking Zeffix.
These medicines must not be taken with Zeffix:
- other medicines containing lamivudine, used to treat HIV infection (sometimes called the AIDS virus)
- emtricitabine used to treat HIV infection or hepatitis B virus infection
- cladribine used to treat hairy cell leukemia
- Tell your doctor if you are being treated with any of these medicines.
Warnings It is important to know that:
Pregnancy
If you are pregnant, suspect or are planning to become pregnant:
- discuss the risks and benefits of taking Zeffix during pregnancy with your doctor. Do not stop taking Zeffix without your doctor's advice.
Feeding time
Zeffix can pass into breast milk. If you are breastfeeding, or plan to breastfeed:
- talk to your doctor before taking Zeffix.
Driving and using machines
Zeffix can make you feel tired, which could affect your ability to drive and use machines.
- Do not drive or operate machinery if you feel tired.
Zeffix contains sugar and preservatives
If you are diabetic, please note that each dose of Zeffix (100 mg = 20 ml) contains 4 g of sucrose.
Zeffix contains sucrose. If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking Zeffix. Sucrose can be harmful to your teeth.
Zeffix also contains preservatives (parahydroxybenzoates) which can cause allergic reactions (which may also occur with delay).
Dose, Method and Time of Administration How to use Zeffix: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Stay in constant contact with your doctor
Zeffix helps control hepatitis B infection. You need to take it every day to control the infection and prevent the disease from getting worse.
- Keep in touch with your doctor, and don't stop taking Zeffix without your doctor's advice.
Quantity to take
The usual dose of Zeffix is 20 ml (100 mg lamivudine) once a day.
Your doctor may prescribe a lower dose if you have kidney problems. An oral solution of Zeffix is available for people who need a lower than recommended dose or who cannot take tablets.
- Talk to your doctor if this applies to you.
If you are already taking another medicine containing lamivudine for HIV infection, your doctor will continue to treat you at the higher dose (usually 150 mg twice a day), as the lamivudine dose of Zeffix (100 mg) does not it is sufficient to treat HIV infection. If you are planning to change your HIV treatment, talk to your doctor about this change first.
Swallow the tablet whole with water. Zeffix can be taken with or without food.
If you forget to take Zeffix
If you forget to take a dose, take it as soon as you remember. Then continue the treatment as before. Do not take a double dose to make up for a forgotten dose.
Don't stop taking Zeffix
You should not stop taking Zeffix without consulting your doctor. There is a risk that your hepatitis will get worse (see section 2). When you stop taking Zeffix your doctor will monitor you for at least four months to check for any problems. This will involve taking blood samples to check for any increases in liver enzyme levels, which may indicate liver damage.
Overdose What to do if you have taken too much Zeffix
Taking too much Zeffix by accident is unlikely to cause any serious problems. If you accidentally take too much, tell your doctor or pharmacist, or contact the nearest hospital emergency department for further advice.
Side Effects What are the side effects of Zeffix
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Side effects that were commonly reported in clinical trials of Zeffix were fatigue, respiratory tract infections, sore throat, headache, stomach upset and pain, nausea, vomiting and diarrhea, increases in liver enzymes and enzymes. products in the muscles (see below).
Allergic reaction
These are rare (may affect up to 1 in 1000 people). The signs include:
- swelling of the eyelids, face or lips
- difficulty swallowing or breathing.
- Contact your doctor immediately if you get these symptoms. Stop taking Zeffix.
Side effects believed to be caused by Zeffix
A very common side effect (these may affect more than 1 in 10 people) that may show up in blood tests is:
- an increase in the level of some liver enzymes (transaminases) which may be a sign of inflammation or damage to the liver.
A common side effect (these may affect up to 1 in 10 people) is:
- cramps and muscle aches
- rash or hives anywhere on the body
A common side effect that may show up in blood tests is:
- an increase in the level of an enzyme produced in the muscles (creatine phosphokinase), which can be a sign of tissue damage.
A very rare side effect (these may affect up to 1 in 10,000 people) is:
- lactic acidosis (excess lactic acid in the blood).
Other side effects
Other side effects have occurred in very small numbers of people but their exact frequency is not known:
- breakdown of muscle tissue
- worsening of liver disease after stopping Zeffix or during treatment if the hepatitis B virus becomes resistant to Zeffix. This can be fatal in some people.
A side effect that may show up in blood tests is:
- a reduction in the number of cells involved in blood clotting (thrombocytopenia).
If you experience side effects
- Tell your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister.
Do not store above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Zeffix contains
The active ingredient is lamivudine. Each film-coated tablet contains 100 mg of lamivudine.
The other ingredients are: microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, macrogol 400, polysorbate 80, synthetic yellow and red iron oxides.
What Zeffix looks like and contents of the pack
Zeffix film-coated tablets are supplied in security seal cartons containing aluminum blisters of 28 or 84 tablets.
The tablets are caramel-colored, film-coated, capsule-shaped, biconvex, debossed with "GX CG5" on one side.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ZEFFIX 5 MG / ML ORAL SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of the oral solution contains 5 mg of lamivudine
Excipients with known effects:
Sucrose 20% (4 g / 20 ml)
Methyl parahydroxybenzoate (E218) 1.5 mg / ml
Propyl parahydroxybenzoate (E216) 0.18 mg / ml
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Oral solution.
Clear, colorless to pale yellow.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Zeffix is indicated for the treatment of chronic hepatitis B in adult patients with:
• compensated liver disease with evidence of active viral replication, persistently elevated serum levels of alanine aminotransferase (ALT) 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 to resistance 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).
04.2 Posology and method of administration
Dosage
Zeffix therapy should be started by a doctor experienced in the treatment of chronic hepatitis B.
Adults: The recommended dose of Zeffix is 100 mg once a day.
In patients with decompensated liver disease, lamivudine should always be used in combination with a second antiviral agent without cross-resistance to lamivudine to reduce the risk of resistance and 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 (disappearance of HBeAg and HBV DNA with detection of HBeAb) has been confirmed, to limit the risk of virological relapse or until HBsAg seroconversion or loss of efficacy occurs (see section 4.4). Serum ALT and HBV DNA levels should be monitored regularly after discontinuation of treatment to detect any late virological relapse.
• in patients with HBeAg negative CHB (pre-core mutants) without cirrhosis, treatment should be given at least until HBs seroconversion or if there is evidence of loss of efficacy. With prolonged treatment, regular monitoring is recommended to confirm that continuation of the chosen therapy remains appropriate for the patient.
• discontinuation of treatment is not recommended in patients with decompensated liver disease or cirrhosis and in those undergoing liver transplantation (see section 5.1).
Upon discontinuation of Zeffix, patients should be monitored periodically for relapsing hepatitis (see section 4.4).
Clinical resistance: in patients with CHB, both HBeAg positive and HBeAg negative, the development of the YMDD (tyrosine-methionine-aspartate-aspartate) mutant of HBV can lead to a decreased therapeutic response to lamivudine, evidenced by an increase in HBV DNA and ALT compared to previous levels on treatment. To reduce the risk of resistance in patients treated with lamivudine monotherapy treatment modification should be considered if HBV DNA remains detectable at 24 weeks or more of treatment. In patients with YMDD mutant of HBV this should be considered. the addition of an alternative agent without cross-resistance to lamivudine (see section 5.1).
Special populations
Pediatric population
The safety and efficacy of Zeffix in children and adolescents below 18 years of age 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.
Kidney failure
In patients with moderate to severe renal impairment, lamivudine serum concentrations (AUC) are increased due to decreased renal clearance. The dosage should therefore be reduced in patients with creatinine clearance below 50 ml / minute. If doses below 100 mg are required, Zeffix oral solution should be used (see Table 1 below).
Table 1: Dosage of Zeffix in patients with reduced renal clearance.
Available data in patients undergoing intermittent hemodialysis (for a duration of less than or equal to 4 hours of dialysis 2-3 times per week) indicate that after reducing the initial lamivudine dose to compensate for creatinine clearance, no no other dosage changes needed.
Hepatic insufficiency
Data obtained in patients with hepatic insufficiency, including those with advanced liver disease awaiting transplantation, show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dosage adjustment is necessary in patients with hepatic insufficiency unless accompanied by renal insufficiency.
Method of administration
Zeffix can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Lamivudine has been given to children (2 years and older) and adolescents with compensated chronic hepatitis B. However, due to data limitations, the administration of lamivudine in this patient population is currently not recommended (see section 5.1).
The efficacy of lamivudine in patients with concomitant Delta hepatitis or hepatitis C infection has not been established and caution is recommended.
There are limited data on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those receiving concomitant immunosuppressive regimens, including cancer chemotherapy. Lamivudine should be used with caution in such patients.
Patients should be monitored regularly during therapy with Zeffix. 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.
Exacerbation of hepatitis
Flare-up during treatment: Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by transient elevations in serum ALT. After initiation of antiviral therapy, serum ALT may increase in some patients while serum HBV DNA levels decrease. In patients with compensated liver disease these elevations in serum ALT were generally not accompanied by increased serum bilirubin concentrations or signs of hepatic decompensation.
With prolonged therapy, HBV viral sub-populations with reduced susceptibility to lamivudine (HBV YMDD mutant) have been identified. In some patients the development of the HBV YMDD mutant can lead to exacerbation of hepatitis evidenced mainly by elevated serum values ALT and return of HBV DNA (see section 4.2). In patients with the presence of the HBV YMDD mutant, the addition of a second agent without cross-resistance to lamivudine should be considered (see section 5.1).
Exacerbation after discontinuation of treatment: acute exacerbation of hepatitis was observed in patients who had discontinued therapy for hepatitis B and was generally evidenced by the increase in serum ALT and the reappearance of HBV-DNA. In controlled phase III studies with no active follow-up treatment, the incidence of ALT elevations after treatment (more than three times baseline) was higher in lamivudine-treated patients (21%) than in those who received placebo (8%). However, the percentage of patients who had post-treatment elevations associated with elevations in bilirubin was lower and similar in both treatment groups. See Table 3 in section 5.1 for further information on frequency of post-treatment ALT elevations. For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events were self-limiting, however they occurred. some deaths have been observed. If Zeffix is discontinued, patients should be monitored periodically both clinically and through test evaluation. t serum liver function (ALT and bilirubin levels) for at least four months, and thereafter as required by clinical practice.
Exacerbation in patients with decompensated cirrhosis: Transplant recipients and patients with decompensated cirrhosis are at increased risk of active viral replication.Due to impaired liver function in these patients, reactivation of hepatitis due to discontinuation of lamivudine or loss of efficacy during treatment may result in severe, even fatal decompensation. These patients should be monitored for clinical, virological and serological parameters. associated with hepatitis B, for renal and hepatic function and antiviral response during treatment (at least every month), and, if treatment is stopped for any reason, for at least 6 months after treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, BUN, creatinine and virological status: HBV antigens / antibodies, and where possible, serum DNA concentrations of "HBV. Patients who experience signs of hepatic failure during or after treatment should be monitored more frequently as deemed appropriate.
For patients who have evidence of recurrent hepatitis after treatment, there are insufficient data on the benefit of re-initiation of lamivudine.
HIV co-infection
In patients co-infected with HIV and receiving, or about to receive, lamivudine therapy or the lamivudine / zidovudine combination, the lamivudine dose prescribed for HIV infection (typically 150 mg twice daily) should be maintained. day in combination with other antiretrovirals). In HIV co-infected patients who do not require antiretroviral therapy, there is a risk of HIV mutation when lamivudine is used alone to treat chronic hepatitis B.
Transmission of hepatitis B
There is no information on maternal-fetal transmission of hepatitis B virus in pregnant women treated with lamivudine. The normal procedures recommended for immunization against hepatitis B virus in children should be followed.
Patients should be advised that lamivudine therapy has not been shown to reduce the risk of hepatitis B virus transmission. Therefore, adequate precautions should continue to be taken.
Intolerance to excipients
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicine.
The diabetic patient should bear in mind that each dose of oral solution (100 mg = 20 ml) contains 4 g of sucrose.
The oral solution contains propyl and methyl parahydroxybenzoate. These substances can cause an allergic reaction in some individuals. This reaction can be delayed.
Lactic acidosis and severe hepatomegaly with steatosis
Cases of lactic acidosis (in the absence of hypoxemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. Since Zeffix is a nucleoside analogue this risk cannot be excluded. Treatment with Nucleoside analogues should be discontinued if there is a rapid rise in aminotransferase levels, progressive hepatomegaly or metabolic / lactic acidosis of unknown aetiology. Non-serious symptoms affecting the digestive system such as nausea, vomiting and abdominal pain may be indicative of development of lactic acidosis. Serious cases, sometimes with a fatal outcome, have been associated with pancreatitis, hepatic failure / fatty liver disease, renal failure and elevated serum lactate levels. Caution should be exercised when prescribing nucleoside analogues to patients (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and fatty liver disease (including some medicines and alcohol). Patients concomitantly infected with hepatitis C and treated with alpha interferon and ribavirin may pose a particular risk. Such patients must be carefully followed.
Mitochondrial dysfunction
It has been shown that both nucleoside and nucleotide analogues are in vivo that in vitro cause a varying degree of mitochondrial damage. Cases of mitochondrial dysfunction have been reported in neonates exposed to nucleoside analogues in utero and / or after birth. The main adverse events reported are haematological disorders (anemia, neutropenia), metabolic disorders (hyperlactataemia and hyperlipasemia). Delayed onset neurological disorders (hypertonia, convulsions, behavioral abnormalities) have been reported. Neurological disorders could be transient or permanent. Each child exposed in utero to nucleoside and nucleotide analogues, should undergo clinical and laboratory follow-up and should be thoroughly monitored for possible mitochondrial dysfunction in the event of the appearance of related signs and symptoms.
Zeffix must not be taken with any other medicines containing lamivudine or medicines containing emtricitabine.
The combination of lamivudine with cladribine is not recommended (see section 4.5).
04.5 Interactions 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, low plasma protein binding and almost complete renal elimination of the substance in its unchanged form.
Lamivudine is predominantly eliminated by active cationic secretion. The possibility of interactions with other concomitantly administered medicinal products should be considered, particularly if their primary route of elimination is active renal secretion by means of the organic cation transport system eg trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are only partially eliminated by this mechanism and have not been shown to interact with lamivudine.
Substances mainly excreted via the active organic anion system or via glomerular filtration hardly give rise to clinically significant interactions with lamivudine. Administration of trimethoprim / sulfamethoxazole 160 mg / 800 mg results in an approximately 40% increase in lamivudine plasma levels. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. However, no dose modification of lamivudine is required unless the patient has renal insufficiency.
A slight increase in Cmax (28%) of zidovudine was observed when administered in combination with lamivudine; however, overall exposure (AUC) is not significantly altered. Zidovudine has no effect on lamivudine pharmacokinetics (see section 5.2).
Lamivudine does not exhibit any pharmacokinetic interaction with alpha-interferon when the two medicinal products are co-administered. However, no formal interaction studies have been performed.
Cladribine: in vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of loss of efficacy of cladribine when combined in the clinical setting.
Some evidence also supports a possible interaction between lamivudine and cladribine. Therefore, co-administration of lamivudine with cladribine is not recommended (see section 4.4).
04.6 Pregnancy and lactation
Pregnancy
A large amount of data on pregnant women (more than 1000 exposure cases) do not indicate any toxicity related to malformations. Zeffix can be used in pregnancy if clinically needed.
For patients who are treated with lamivudine and subsequently become pregnant, the possibility of a recurrence of hepatitis following discontinuation of lamivudine should be considered.
Feeding time
Based on more than 130 mother / child pairs being treated for HIV, serum concentrations of lamivudine in breastfed infants from mothers being treated for HIV are very low (approximately 0.06-4% of maternal serum concentrations ) and progressively decline to undetectable levels as breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and therefore this is likely to lead to exposures exerting a sub-optimal antiviral effect. Maternal hepatitis B does not lead to a contraindication to breastfeeding if the infant is adequately managed for the prevention of hepatitis B at birth and there is no evidence that the low concentration of lamivudine in breast milk leads to undesirable effects in breastfed infants. Breastfeeding may therefore be considered in nursing mothers treated with lamivudine for HBV taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother. If there is maternal transmission of HBV, despite adequate prophylaxis, interruption of breastfeeding should be considered to reduce the risk of emergence of lamivudine-resistant mutants in the neonate.
Fertility
No data available.
Mitochondrial dysfunction
It has been shown that both nucleoside and nucleotide analogues are in vivo that in vitro cause a varying degree of mitochondrial damage. Cases of mitochondrial dysfunction have been reported in neonates exposed to nucleoside analogues in utero and / or after birth (see section 4.4).
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
04.8 Undesirable effects
The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations in ALT and CPK, see below) were similar between patients treated with placebo and those treated with lamivudine. The most commonly reported adverse reactions were malaise and fatigue, respiratory tract infections, sore throat and tonsillar discomfort, headache, abdominal pain or cramps, nausea, vomiting and diarrhea.
Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered at least possibly causally related to lamivudine. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 a
The frequency categories assigned to the adverse reactions are primarily based on experience from clinical trials involving a total of 1171 chronic hepatitis B patients treated with lamivudine 100 mg.
* The frequency observed in phase III clinical trials in the lamivudine group was not greater than that observed in the placebo group.
Cases of pancreatitis and peripheral neuropathies (or paraesthesia) have been reported in HIV-infected patients. In patients with chronic hepatitis B, no difference in the incidence of these events was observed between patients treated with lamivudine and placebo.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported during combination therapy with nucleoside analogues in HIV patients.
Rare cases of lactic acidosis have been reported in patients treated with lamivudine for hepatitis B.
04.9 Overdose
Administration of lamivudine at particularly high doses in acute animal toxicity studies did not result in any organ toxicity. There are limited data available on the consequences of acute oral overdose in humans. There were no deaths and patients recovered. No specific signs or symptoms were identified following overdose.
In the event of an overdose, the patient should be monitored and given appropriate standard supportive treatment. Continuous hemodialysis, although not studied, can be used in the treatment of overdose as lamivudine is dialysable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides reverse transcriptase inhibitors.
ATC code: J05AF05.
Lamivudine is an antiviral agent active against the hepatitis B virus in all cell lines tested and in experimentally infected animals.
In both healthy and infected cells, lamivudine is metabolised to its triphosphate derivative (TP), which is the active form of the parent product. The intracellular half-life of triphosphate in hepatocytes is 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the viral HBV polymerase.
The formation of further viral DNA is blocked by the incorporation of lamivudine-TP into the chain and its subsequent termination.
Lamivudine-TP does not interfere with the normal cellular metabolism of deoxynucleotides. It is also only a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on the DNA content of mammalian cells.
In assays on the potential effects of substances on mitochondrial structure and DNA content and function, lamivudine was found to have no appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not incorporated into mitochondrial DNA permanently and does not act as an inhibitor of mitochondrial DNA polymerase gamma.
Clinical experience
Experience in patients with HBeAg positive CHB and compensated liver disease: In controlled studies, one year of lamivudine therapy significantly suppressed HBV DNA replication [34-57% of patients were below the test detection limits (Abbott Genostics solution hybridization test, LLOD pg / ml)], normalized ALT levels (in 40-72% of patients), induced HBeAg seroconversion (loss of HBeAg and detection of HBeAb with loss of HBV DNA [by conventional tests], in 16- 18% of patients), improved histological picture (38-52% of patients had a ≥ 2 point decrease according to the Knodell Histological Activity Index [HAI]) and reduced progression to fibrosis (in 3 -17% of patients) and progression to cirrhosis.
Prolonged lamivudine treatment for an additional two years in patients who were unable to achieve HBeAg seroconversion in the initial 1-year controlled studies showed further improvement in bridging fibrosis. In patients with HBV YMDD mutant, 41/82 (50%) patients had an improvement in liver inflammation parameters, 40/56 (71%) patients without HBV YMDD mutant had an improvement. Improvement in bridging fibrosis occurred in 19/30 (63%) patients without the YMDD mutant and in 22/44 (50%) patients with the mutant. Five percent (3/56) of patients without YMDD mutant and 13% (11/82) of patients with YMDD mutant showed worsening in liver inflammation parameters compared to the pre-treatment situation. Progression to cirrhosis occurred in 4/68 (6%) patients with the YMDD mutant, while no patient without the mutant had progression to cirrhosis.
In an extended treatment study in Asian patients (NUCB3018) the HBeAg seroconversion rate and ALT normalization rate at the end of the 5-year treatment period was 48% (28/58) and 47% (15 / 32). HBeAg seroconversion was increased in patients with elevated ALT levels: 77% (20/26) of patients with ALT> 2 ULN prior to treatment had seroconversion. At the end of 5 years, all patients had HBV DNA levels that were either undetectable or below pre-treatment levels.
Additional results from the study distributed based on the presence of the YMDD mutant are summarized in Table 2.
Table 2: 5-Year Efficacy - Results Based on Presence / Absence of YMDD Mutant (Asian Study) NUCB3018
1. Patients marked as YMDD mutants were those with HBV YMDD mutant ≥ 5% at at least one annual test during the 5-year period. Patients classified as non-YMDD mutants were those with a percentage of wild HBV virus > 95% in all annual tests during the 5-year study period.
2. upper limits of the norm
3. Abbott Genostics Solution Hybridization Test (LLOD
4. Chiron Quantiplex test (LLOD 0.7 Meq / ml)
Comparison data based on the presence of the YMDD mutant were also available for histological analysis but only for up to three years. In patients with the HBV YMDD mutant, 18/39 (46%) had improvements in necroinflammatory activity and 9 / 39 (23%) worsened. In patients without the mutant, 20/27 (74%) had improvements in necroinflammatory activity and 2/27 (7%) worsened.
Following HBeAg seroconversion, serological response and clinical remission are generally lasting after lamivudine discontinuation. However, relapse may occur following seroconversion. In a long-term follow-up study, in patients who had had previous seroconversion and discontinued lamivudine, late virological relapse occurred in 39% of subjects. Therefore, after HBeAg seroconversion, patients should be monitored periodically to assess that serological and clinical responses are maintained. Prolonged serological response is maintained. Retreatment with either lamivudine or an alternative antiviral drug should be considered to reestablish clinical control of HBV.
In patients followed up for up to 16 weeks after stopping treatment at one year, post-treatment ALT elevations were seen more frequently in those treated with lamivudine than in those who received placebo. A post-treatment comparison of ALT elevations between week 52 and week 68 in patients who discontinued lamivudine at week 52 and patients who received placebo throughout the course of treatment in the same studies is shown in Table 3. The proportion of patients who had post-treatment ALT elevations with increased bilirubin levels was low and similar in patients exposed to both lamivudine and placebo.
Table 3: Post-treatment ALT elevations in 2 placebo-controlled studies in adults
* Each patient can be represented in one or more categories
† Comparable to Grade 3 toxicity according to modified WHO criteria
ULN = upper limit of normal
Experience in patients with CHB HBeAg negative: Preliminary data indicate that the efficacy of lamivudine in HBeAg negative CHB patients is similar to that in HBeAg positive CHB patients with 71% of patients having HBV DNA suppression below the test detection limit, 67% normalization of ALT and 38% with improvement in HAI after one year of treatment. When lamivudine was withdrawn, most patients (70%) showed resumption of viral replication. The data are derived from a prolonged treatment study (NUCAB3017) in HBeAg negative patients treated with lamivudine. After two years of treatment in this study, ALT normalization and HBV DNA undetectable occurred in 30/69 (43%) and 32/68 (47%) patients respectively, while the improvement in necroinflammatory score was highlighted in 18/49 (37%) patients. In patients without the HBV YMDD mutant, 14/22 (64%) patients showed improvement in the necroinflammatory index and 1/22 (5%) patients had worsened compared to the pre-treatment situation. In patients with the mutant, 4/26 (15%) patients showed improvement in the necroinflammatory index and 8/26 (31%) patients worsened from the pre-treatment situation. Neither patient in either group progressed. to cirrhosis.
Emergency frequency of HBV YMDD mutant and impact on treatment response: lamivudine monotherapy leads to selection of the HBV YMDD mutant in approximately 24% of patients after one year of therapy, which increases to 69% after 5 years of therapy. Development of the HBV YMDD mutant is associated with a reduced response to treatment in some patients as evidenced by increased levels of HBV DNA and elevation of ALT compared to previous levels during treatment, progression of signs and symptoms of hepatitis and / or worsening of hepatic necroinflammation indices. Optimal therapeutic management of patients with HBV YMDD mutant has not yet been established (see section 4.4).
In a double-blind study, in patients with HBV YMDD mutant CHB and compensated liver disease (NUC20904), with a reduced virological and biochemical response to lamivudine (n = 95), the addition of adefovir dipivoxil 10 mg once per day at the current lamivudine 100 mg regimen for 52 weeks resulted in a median reduction in HBV DNA of 4.6 log10 copies / ml compared to a median increase of 0.3 log10 copies / ml in patients treated with lamivudine alone . Normalization of ALT levels occurred in 31% (14/45) of patients treated with combination therapy compared with 6% (3/47) of patients treated with lamivudine alone. Viral suppression was maintained (follow-on study NUC20917) with combination therapy during the second year of treatment at week 104 with patients continuing to improve in virological and biochemical response.
In a retrospective study to determine factors associated with HBV DNA elevation, 159 HBeAg positive Asian patients were treated with lamivudine and followed for a mean of at least 30 months. Those patients with HBV DNA levels greater than 200 copies / mL at 6 months (24 weeks) of lamivudine therapy had a 60% chance of developing the YMDD mutant compared with 8% of those with lower HBV DNA levels. at 200 copies / mL at 24 weeks of lamivudine therapy The risk of developing the YMDD mutant was 63% compared to 13% with a limit of 1000 copies / mL (NUCB3009 and NUCB3018).
Experience in patients with decompensated liver disease: placebo-controlled studies were not undertaken in patients with decompensated liver disease because they were considered inappropriate. In uncontrolled studies, in which lamivudine was administered before and during transplantation, "effective suppression of" HBV DNA and normalization of ALT was demonstrated. When lamivudine therapy was continued after transplantation, there was a decrease in the rate of HBV reinfection of the transplant, an increase in HBsAg loss and a one-year survival rate of 76-100%.
As expected, due to concomitant immunosuppression, the onset rate of HBV YMDD mutants after 52 weeks of treatment was higher (36% - 64%) in the liver transplant population than in immunocompetent CHB patients (14 % - 32%).
Forty patients (HBeAg negative or HBeAg positive) with either decompensated liver disease or HBV recurrence after liver transplantation and YMDD mutant were enrolled in an open-label arm of study NUC20904. Addition of 10 mg adefovir dipivoxil once per day at the current lamivudine regimen of 100 mg for 52 weeks, showed a median decrease in HBV DNA of 4.6 log10 copies / ml. There was also an improvement in liver function after one year of therapy. viral suppression was maintained (follow-on study NUC20917) with combination therapy during the second year of treatment at week 104 and most patients had improvement in markers of liver function and continued to benefit from clinical .
Experience in CHB patients with advanced fibrosis or cirrhosis: in a placebo-controlled study in 651 patients with clinically compensated chronic hepatitis B and histologically confirmed fibrosis or cirrhosis, lamivudine treatment (median duration 32 months) significantly reduced the level of overall disease progression (34/436, 7.8% for lamivudine versus 38/215, 17.7% for placebo, p = 0.001), demonstrated by a significant reduction in the proportion of patients who had increased Child-Pugh values (15/436, 3, 4% versus 19/215, 8.8%, p = 0.023) or who developed hepatocellular carcinoma (17/436, 3.9% versus 16/215, 7.4%, p = 0.047). The overall disease progression rate in the lamivudine group was higher in subjects with the presence of the HBV YMDD mutant (23/209, 11%) compared to those without the presence of the HBV YMDD mutant (11/221, 5%). However, disease progression in YMDD mutant subjects in the lamivudine group was lower than disease progression in the placebo group (23/209, 11% versus 38/214, 18% respectively). Confirmed HBeAg seroconversion occurred in 47% (118/252) of subjects treated with lamivudine and 93% (320/345) of subjects taking lamivudine became HBV DNA negative (VERSANT [version 1], bDNA test, LLOD
Experience in children and adolescents: Lamivudine was given to children and adolescents with compensated CHB in a placebo-controlled study of 286 patients aged 2-17 years. This population consisted mostly of children with minimal hepatitis B. A dosage of 3 mg / kg once daily (up to a maximum of 100 mg daily) has been used in children 2 to 11 years of age and a dosage of 100 mg once daily in adolescents of age 12 or older. This assay needs to be further validated. The difference in HBeAg seroconversion indices (disappearance of HBeAg and HBV DNA with detection of HBeAb) between the placebo and lamivudine groups was not statistically significant in this population (the indices after one year were 13% (12 / 95) for the placebo group versus 22% (42/191) for the lamivudine group; p = 0.057). The incidence of the HBV YMDD mutant was similar to that observed in adults with a range from 19%, at week 52, up to 45% in patients treated continuously for 24 months.
05.2 Pharmacokinetic properties
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 to peak (Tmax) of maximum serum concentration (Cmax) is approximately 1 hour. At therapeutic doses, ie 100 mg / day, the Cmax is of the order of 1.1-1.5 mcg / ml, and the minimum values are 0.015-0.020 mcg / ml.
Co-administration of lamivudine with food results in a delay in Tmax and a decrease in Cmax (reduced by up to 47%). However, as the rate (calculated from AUC) of lamivudine absorbed is not affected, lamivudine can be administered with or without food.
Distribution: Studies following intravenous administration show that the mean volume of distribution is 1.3 l / kg. Lamivudine exhibits linear pharmacokinetics in the therapeutic dose range and exhibits a low percentage of plasma binding to albumin.
Limited data show that lamivudine enters the central nervous system and reaches the cerebrospinal fluid. The mean ratio between the concentration of lamivudine in CSF and serum, 2-4 hours after oral administration, is about 0.12.
Biotransformation: Lamivudine is excreted, unchanged, primarily via the kidney. Due to limited hepatic metabolism (5-10%) and reduced plasma protein binding, the likelihood of metabolic interactions of other substances with lamivudine is low.
Elimination: The mean systemic clearance of lamivudine is approximately 0.3 l / h / kg. The mean elimination time observed is between 5 and 7 hours. Lamivudine is predominantly excreted unchanged in the urine via glomerular filtration and active secretion (organic cation transport system). Renal clearance accounts for 70% of lamivudine elimination.
Special Patient Categories: Studies in patients with renal insufficiency show that lamivudine elimination is affected by renal dysfunction. A dose reduction is required in those patients with creatinine clearance below 50 ml / min (see section 4.2).
The pharmacokinetics of lamivudine are not affected by hepatic dysfunction. Limited data in liver transplant patients show that hepatic decompensation does not significantly affect lamivudine pharmacokinetics unless accompanied by renal dysfunction.
Based on the pharmacokinetic profile of lamivudine it is conceivable that in elderly patients normal aging with concomitant decline in renal function has no significant clinical effect on lamivudine exposure, if we exclude patients with creatinine clearance below 50 ml / min ( see section 4.2).
05.3 Preclinical safety data
In animal toxicity studies, the administration of lamivudine at high doses was not associated with any relevant organ toxicity. At higher doses, minor effects on indicators of liver and kidney function were observed, as well as occasional reductions in liver weight.
A reduction in the number of erythrocytes and neutrophils was identified as the probably most clinically relevant effect. These events were rarely reported in clinical trials.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, exhibited activity in a cytogenetic test in vitro and in the mouse lymphoma test. Lamivudine is not genotoxic in vivo at doses that induce plasma concentrations approximately 60-70 times higher than the plasma levels expected in the clinical setting. As the mutagenic activity in vitro of lamivudine was not confirmed by testing in vivo, it follows that lamivudine is not expected to pose a genotoxic risk to patients under treatment.
Reproduction studies in animals have shown no teratogenicity or effect on male or female fertility. When administered to pregnant rabbits, at exposure levels comparable to those achieved in humans, lamivudine induces early embryo lethality. This does not occur in the rat even at very high systemic exposures.
The results of long-term carcinogenicity studies with lamivudine in rats and mice did not show any carcinogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sucrose (20% w / v)
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Citric acid (anhydrous)
Propylene glycol
Sodium citrate
Artificial strawberry flavor
Artificial banana flavor
Purified water
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
After first opening: 1 month
06.4 Special precautions for storage
Store at a temperature not exceeding 25 ° C
06.5 Nature of the immediate packaging and contents of the package
Pack containing 240 ml lamivudine oral solution in an opaque white high density polyethylene (HDPE) bottle with a child resistant polypropylene closure. The pack also contains a polyethylene syringe adapter and a 10 ml oral dosing syringe consisting of a polypropylene cylindrical body (with ml graduations) and a polyethylene plunger.
The oral dosing syringe is provided to accurately dose the prescribed amount of oral solution. The instructions for use are attached to the package.
06.6 Instructions for use and handling
Unused medicine should be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Glaxo Group Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/99/114/003
034506030
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 29 July 1999
Date of last renewal: 27 August 2009
10.0 DATE OF REVISION OF THE TEXT
January 2014
