Traits

Lamivudine's chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-1H-pyrimidin-2-one. Molecular formula is C8H11N3O3S, molecular weight is 229.26.

This product is film-coated tablets, after removing the film coat appears white.

Pharmacological effects

Lamivudine is a nucleoside analog, which can be phosphorylated intracellularly to lamivudine triphosphate (L-TP) and embedded in viral DNA in the form of cyclic adenosine phosphate through hepatitis B virus (HBV) polymerase, resulting in the suspension of DNA strand synthesis. Lamivudine triphosphate is a weak inhibitor of mammalian α, β, and γ-DNA polymerase. In in vitro experiments, lamivudine triphosphate has a half-life of 17-19 hours in hepatocytes.

Lamivudine is an antiviral agent that has demonstrated inhibition of hepatitis B virus in a variety of experimental cell lines and animal models of infection. However, two of these animal models (ducklings and chimpanzees) showed rebound in serum DNA levels of hepatitis B virus within 4 and 14 days, respectively, after cessation of treatment with the product.

Long-term use of lamivudine can lead to a decrease in HBV sensitivity to it. Genotypic analysis of viral strains showed that such changes were associated with the substitution of methionine by valine or isoleucine at site 552 and leucine by methionine at site 528 of the YMDD sequence in the catalytic reaction region of HBV polymerase. In vitro, HBV recombinants containing the YMDD variant are less able to replicate than wild-type HBV, and it is not known whether the other variants of HBV are associated with their reduced sensitivity to lamivudine in vitro.

Clinical Studies A placebo-controlled study in 440 HBeAg-positive patients with chronic hepatitis B in China showed that lamivudine treatment for 1 year resulted in HBV DNA conversion in 71% of the patients and normalization of alanine aminotransferase [ALT] in 71% of the patients.HBeAg seroconversion rates (HBeAg conversion with HBeAb emergence) increased with prolongation of treatment. The HBeAg seroconversion rates (HBeAg conversion, HBeAb appearance) increased with the duration of treatment, with the HBeAg seroconversion rates in patients with abnormal pre-treatment ALTs being 13%, 22%, 30%, and 37%, respectively, at 1, 2, 3, and 4 years after treatment. An expanded clinical study in 2,200 patients in China showed that 1 year of lamivudine treatment resulted in HBV DNA conversion in 80% of patients, normalization of ALT in 72%, seroconversion of HBeAg in 16%, and hepatic histologic improvement in 54% of patients.

In controlled studies abroad, HBeAg-positive patients treated with lamivudine for 1 year showed that 34-57% of patients had HBV DNA conversion, 40-72% had normal ALT, 16-18% had HBeAg seroconversion, and 38-52% had liver histologic improvement, which slowed down the progression of liver fibrosis in some patients ( Progression of liver fibrosis occurred in 3-17% of patients in the lamivudine group, compared with 7-27% in the placebo group) and to cirrhosis (1.8% of patients in the lamivudine group, compared with 7.1% in the placebo group). After continuation of treatment for two years in patients who did not achieve HBeAg seroconversion on lamivudine for 1 year, liver inflammation improved in 60% of these patients and bridging fibrosis improved in 51%.

In patients who did not achieve HBeAg seroconversion on therapy, discontinuation of lamivudine therapy may result in reproduction of HBV replication, as evidenced by a return of HBVDNA and serum ALT levels to pretreatment levels within 2 to 6 months after discontinuation.

Hepatitis B virus YMDD variants are detected with increasing duration of lamivudine treatment, and the incidence increases with duration of treatment; 20% after 1 year, 53% after 3 years, and 70% after 4 years of treatment, and may be higher in immunocompromised patients. With the emergence of the YMDD variant, some patients had a reduced response to lamivudine therapy (including lower rates of HBeAg seroconversion and disappearance). 1-year studies have shown that: compared with the placebo group, serum HBVDNA and ALT levels remained significantly lower, hepatic histology improved markedly, and the HBeAg seroconversion rate reached 17-20% (compared with only 6-7% in the placebo group). ). At the same time, the majority of patients continued to have lower HBV DNA and ALT levels than before treatment. Continuing lamivudine therapy in these patients, their HBV DNA and ALT remained controlled below pre-treatment levels. In addition, the occurrence of adverse events was similar in patients who developed the YMDD variant compared to patients without the YMDD variant. In vivo studies have shown that YMDD variant HBV exhibits reduced replicative capacity, with 53% converting to wild-type HBV within 4 months of discontinuing treatment.

In HBeAg-negative patients infected with the pre-C-region variant strain of HBV, preliminary findings suggest that the one-year efficacy of lamivudine is similar to the efficacy of treating patients who are HBeAg-positive (wild-type HBV-infected), i.e. After 1 year of treatment, HBVDNA was suppressed in 71% of patients; ALT normalization was achieved in 67% of patients; and Knodell HAI scores for liver histology improved in 38% of patients. Viral replication resumed in the majority of HBeAg-negative patients after lamivudine treatment was discontinued after 1 year. Limited data suggest that prolonged lamivudine therapy (2 years) in this population maintains HBV DNA suppression with normal ALT. The incidence of serious adverse events during treatment and after discontinuation was low and similar in HBeAg-negative patients with or without the YMDD variant.

Placebo-controlled clinical studies are not appropriate in patients with decompensated liver disease. Open treatment studies in this population have shown that patients treated with lamivudine before and during liver transplantation effectively suppress serum HBV DNA levels and normalize serum ALT. After liver transplantation, continuation of lamivudine reduces HBV reinfection in the transplanted liver, with increased HBsAg negativity and a 1-year survival rate of 76-100%.

As expected, due to concomitant immunosuppression, the incidence of YMDD-variant HBV was higher in the liver transplantation population (36-64%) than in immunologically sound chronic hepatitis B patients (14-32%) after 52 weeks of treatment. However, the presence of the YMDD variant does not necessarily correlate with the course of liver disease, and most patients continue to benefit from continuous lamivudine therapy.

In China, there is no information on the use of lamivudine in children.

Pharmacokinetics

Absorption : Lamivudine is well absorbed by the gastrointestinal tract, with a normal bioavailability of 80-85% in adults after oral administration. After oral administration, the mean time to peak (Tmax) of maximum blood concentration (Cmax) is about 1 hour. Lamivudine given at a therapeutic dose of 100 mg once daily has a maximum blood concentration Cmax of about 1.1-1.5 mg/mL (4.8-6.5 mmol/L) and a trough blood concentration of 0.015-0.020 mg/mL (0.065-0.087 mmol/L).

Lamivudine taken concomitantly with food delays Tmax and decreases Cmax (up to 47%) but does not alter its bioavailability (calculated as the area under the drug-time curve); therefore, the product can be taken both before and after meals.

Distribution : Intravenous administration studies have shown that lamivudine has a mean volume of distribution of 1.3 L/kg, linear pharmacokinetics over the therapeutic dose range, and low plasma protein binding to albumin (<36%). Limited information suggests that lamivudine passes through the central nervous system and enters the cerebrospinal fluid (CSF), with the ratio of cerebrospinal fluid/serum drug concentration averaging approximately 0.12 after 2-4 hours of oral lamivudine administration.

Metabolism : Metabolism is a minor route of clearance of lamivudine, and the only known metabolites of lamivudine in the human body are the transthyretin metabolites. Because of the low degree of hepatic metabolism (5-10%) and low plasma protein binding of lamivudine, the potential for interaction between lamivudine and its metabolites is low.

Excretion : Lamivudine is excreted in the urine, mainly in its original form, by glomerular filtration and secretion (organic cation transport system), with renal clearance accounting for about 70% of its total clearance, the mean systemic clearance being 0.3 L/h/kg, and the clearance half-life being 5-7 hours.

Special populations : Studies in people with renal impairment have shown that renal insufficiency affects lamivudine clearance. The dose should be reduced in patients with creatinine clearance <50 mL/min.

Hepatic impairment has no effect on the pharmacokinetic properties of lamivudine. Limited studies in liver transplant patients have shown that hepatic impairment alone has no effect on the pharmacokinetic properties of lamivudine unless accompanied by renal impairment.

Normal organic aging in the elderly with renal hypoplasia had no clinically significant effect on the pharmacokinetic properties of lamivudine, except at creatinine clearance < 50 mL/min.

Toxicological Studies

Genotoxicity Lamivudine did not show mutagenic activity in microbial mutagenicity assays and in vitro cell transformation assays, but showed weak mutagenic activity in in vitro cultured human lymphocytes and mouse lymphoma assays. No significant genotoxicity was seen in rats given lamivudine 2000 mg/kg orally (blood concentration 60-70 times the recommended clinical dose for patients with chronic hepatitis B).

Reproductive toxicity In rats given lamivudine 4000 mg/kg/day orally (blood concentration 80-120 times the clinical blood concentration in humans), fertility and survival, growth, and development of weaned offspring were not significantly affected.

Rats and rabbits given lamivudine 4000 and 1000 mg/kg/day orally (blood concentrations about 60 times the blood concentration of the recommended human clinical dose) did not show significant teratogenic effects. In rabbits, an increase in early embryonic mortality was observed when blood concentrations were similar to those of the recommended human clinical dose. However, no such phenomenon was observed in rats when the blood concentration reached 60 times the blood concentration of the clinically recommended human dose. Studies in pregnant rats and rabbits have shown that lamivudine can cross the placenta into the fetus. There is no information on adequate and strictly controlled clinical studies of lamivudine in pregnant women.

Lamivudine concentrations in milk of lactating rats were similar to its concentrations in plasma.

Carcinogenicity : The results of long-term carcinogenicity tests in rats and mice showed no significant carcinogenicity at exposure levels up to 34 times (mice) and 200 times (rats) the clinical exposure level in humans.

Indications

Lamivudine tablets are indicated for the treatment of adult patients with chronic hepatitis B with elevated alanine aminotransferase [ALT] and active viral replication who have compensated liver function.

Dosage

This product should be used under the supervision of a physician experienced in the treatment of chronic hepatitis B. The recommended dosage is 100 mg once daily, either before or after meals.

Treatment For HBeAg-positive patients, based on the available research data, it is recommended that treatment with this product should be applied for at least 1 year, and that termination of treatment may be considered if HBeAg seroconversion (i.e., HBeAg conversion and HBeAb positivity) occurs after treatment, HBVDNA conversion, ALT normalization, and consolidation of therapeutic efficacy is confirmed by 2 consecutive tests at least 3 months apart.

For HBeAg-negative patients, for whom an appropriate course of treatment has not been determined, termination of treatment may be considered in the event of HBsAg seroconversion or ineffective treatment (HBV DNA levels or ALT levels remain persistently elevated).

For patients considered to have YMDD mutations, if their HBVDNA and ALT levels remain lower than before treatment, the medication can be continued under close observation and supportive therapy can be intensified as necessary. If their HBV DNA and ALT levels remain above pre-treatment levels, follow-up should be intensified, and appropriate therapies should be adopted by the physician under close monitoring depending on the specific condition. If HBeAg seroconversion and HBVDNA conversion are confirmed after 2 tests at least 3 months apart, termination of treatment may be considered. For patients with hepatic decompensation or cirrhosis in the course of treatment with this product, the drug should not be easily discontinued, and symptomatic hepatoprotective therapy should be strengthened.

If HBV DNA and ALT remain above pre-treatment levels during treatment, and HBeAg seroconversion does not occur in patients who were HBeAg-positive prior to treatment, suggesting that the treatment is ineffective, termination of treatment may be considered. For patients with other clinical indications such as liver histologic examination, patients with disease progression combined with hepatic decompensation or cirrhosis during the course of treatment with this product, the drug should not be easily discontinued, and symptomatic liver-protecting treatment should be strengthened.

If lamivudine treatment is terminated, the patient should be closely followed up by a physician for at least 4 months after discontinuation of the drug (the frequency of follow-up depends on the patient's condition), with regular testing of ALT and bilirubin levels, HBV DNA and HBeAg, to prevent hepatitis recurrence.After 4 months, the patient may be continued to be followed up according to clinical needs.

Persons with renal impairment : Serum lamivudine concentrations (area under the drug-time curve AUC) were elevated after administration of this product in persons with moderate to severe renal impairment due to decreased renal clearance. Considering the accuracy of dose adjustment, lamivudine 100 mg tablets are contraindicated in patients with chronic hepatitis B with serum creatinine clearance < 50 mL/min.

People with Hepatic Impairment : Data from studies in people with severe hepatic impairment, including patients with advanced liver disease awaiting liver transplantation, suggest that hepatic insufficiency alone does not significantly affect the pharmacokinetics of lamivudine, unless the patient has renal impairment. The results of pharmacokinetic studies suggest that no dose adjustment is necessary in patients with moderate or severe hepatic impairment.

Adverse Reactions

A variety of serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly with steatosis, post-treatment exacerbation of hepatitis B, pancreatitis, and emergence of viral variants associated with decreased drug sensitivity and diminished therapeutic response) are also described in the Warnings and Precautions.

Clinical studies in patients with chronic hepatitis B have shown that lamivudine is well tolerated by most patients. The incidence of most adverse events was similar in patients in the lamivudine and placebo groups (see table below for details). The most common adverse events were malaise and malaise, respiratory tract infection, headache, abdominal discomfort and abdominal pain, nausea, vomiting and diarrhea. The following adverse events were also observed in a 2,200-case phase IV clinical study in China: dry mouth in one case, generalized scarlet fever-like rash in one case, decreased phosphocreatine activating enzyme and platelets in one case, and hospitalization for severe hepatitis in one case.

Observations during clinical activities : The following events were observed during the approval of lamivudine for clinical use. Because these events were voluntarily reported from a group of people with an unknown sample size, an estimate of the incidence cannot be made. These events are included because of their severity, frequency of reporting, possible causal relationship with lamivudine, or a combination of all these factors.

Gastrointestinal system : Stomatitis;

Endocrine and metabolic : Hyperglycemia;

Systemic : Weakness;

Hematologic and lymphatic system : Anemia, pure red blood cell aplasia, lymphadenopathy, splenomegaly.

Liver and pancreas : Lactic acidosis and steatosis, pancreatitis, exacerbation of hepatitis at the end of treatment;

Allergy : Allergic reaction, rubella;

Musculoskeletal : Rhabdomyolysis;

Neurologic system : Sensory abnormalities, peripheral neuropathy;

Respiratory system : Abnormal breath sounds/croup.

Skin : Alopecia, pruritus, rash.

Contraindications

It is contraindicated in case of hypersensitivity to lamivudine or any other ingredient in the preparation.

Warnings

Lactic Acidosis/Severe Hepatomegaly with Steatosis : Lactic acidosis, including fatal cases, has been reported in high-dose nucleoside analog combinations for the treatment of HIV-infected patients, usually in combination with severe hepatomegaly and hepatic steatosis. Such events have been reported occasionally in patients with hepatitis B combined with decompensated liver disease, and treatment should be discontinued when clinical signs and laboratory findings suggestive of lactic acidosis occur.

Worsening of hepatitis after completion of treatment: Clinical manifestations and laboratory evidence of worsening of hepatitis have occurred after discontinuation of lamivudine therapy (in addition to the reappearance of HBV DNA, which is often observed after discontinuation of therapy, and is detected mainly by elevation of serum ALT). The incidence of ALT elevations in patients observed 16 weeks after discontinuation of therapy after 1 year of treatment is shown in the table below). Although most events appear to be self-limiting, death has been reported in some cases. It is not clear whether there is a causal relationship with termination of lamivudine therapy. Patients must be closely monitored by clinical follow-up and laboratory follow-up for at least several months after discontinuation of therapy. There is insufficient evidence to determine whether restarting therapy changes the course of hepatitis worsening after treatment.

Pancreatitis : Pancreatitis and peripheral nervous system disease (or sensory abnormalities) have been reported in HIV-infected patients treated with this product.

Precautions

Patients should be cautioned that lamivudine is not a drug that can cure hepatitis B by eradication. It must be administered under the supervision of a physician experienced in the treatment of hepatitis B. Patients should not discontinue the drug and should be monitored regularly during treatment. ALT levels should be measured at least every 3 months, and HBV DNA and HBeAg should be measured every 6 months.

Patients who are positive for HBsAg but have normal ALT levels should not start lamivudine treatment even if they are positive for HBeAg and/or HBV DNA, and should be followed up regularly and reconsidered according to the changes in their condition.

With the prolongation of lamivudine treatment, the YMDD variant of hepatitis B virus can be detected in some patients, and the sensitivity of this variant to lamivudine decreases). If the patient's clinical condition is stable and HBV DNA and ALT levels remain lower than before treatment, treatment can be continued and closely monitored. A small number of patients with the YMDD variant may present with a recurrence of hepatitis due to the reduced effect of lamivudine and may experience a return of HBV DNA and ALT levels to pretreatment levels or above. Some patients with YMDD variant, especially in patients with hepatic decompensation or cirrhosis, have rarely reported disease progression leading to serious consequences or even death in a few cases. Since discontinuation of lamivudine in such cases may also lead to disease progression, it is not advisable to arbitrarily discontinue lamivudine in patients with hepatic decompensation or cirrhosis in the course of lamivudine treatment. Therefore, if a YMDD variant is suspected, increased clinical and laboratory monitoring may be helpful in making treatment decisions.

To date, there is no information on the long-term efficacy of lamivudine in the treatment of hepatitis B in combination with hepatitis D or hepatitis C. There is limited information on lamivudine for the treatment of patients who are HBeAg-negative or who are receiving concomitant immunosuppressive therapy, including oncologic chemotherapy.

If HBeAg-positive patients discontinue the product prior to seroconversion, or in those who discontinue the drug because of poor therapeutic efficacy, it is possible that some patients may experience an exacerbation of hepatitis, primarily in the form of a reappearance of HBV DNA and an elevation of serum ALT.

If lamivudine therapy is discontinued, the patient's clinical condition and serum hepatic function markers (ALT and bilirubin levels) should be monitored regularly for at least 4 months, followed by follow-up as clinically indicated. There is insufficient information on restarting lamivudine therapy in patients who experience a recurrence of hepatitis after discontinuation of therapy.

The risk of viral replication is greater and the prognosis is poorer in patients who have undergone organ transplantation or have advanced liver disease such as decompensated cirrhosis. Safety and efficacy have not been established in this group of patients. There are insufficient clinical studies to authorize the use of lamivudine in the treatment of patients who have received organ transplants or have advanced liver disease such as decompensated cirrhosis. According to overseas clinical studies, the rational use of lamivudine can improve the recent survival rate of patients with decompensated liver function, in these patients, it is not advisable to stop lamivudine. However, as an antiviral drug, lamivudine cannot reverse the end-stage changes in liver structure and its complications, so other (including liver transplantation) more effective treatments should be considered for these patients. In patients with HIV co-infection who are receiving or intend to receive lamivudine or lamivudine-zidovudine combination therapy, the recommended dose of lamivudine for HIV infection should be maintained (usually 150 mg twice daily in combination with other antiretroviral agents). In patients with concurrent HIV infection who do not require antiretroviral therapy, such as lamivudine alone for chronic hepatitis B, there is a potential for HIV mutations.

There is no information on the use of this product in pregnant women, so routine immunization of newborns with hepatitis B vaccine should still be performed.

Effects on driving and ability to operate machinery : There are no studies on the effects of lamivudine on the ability to drive or operate machinery. Also, the results of pharmacologic studies of the drug do not accurately predict that lamivudine has adverse effects on these activities.

Medication for Pregnant and Nursing Women

Pregnancy : The safety of this product in pregnant women has not been established. Reproduction studies in animals have shown it to be non-teratogenic and to have no effect on the fertility of females or males. When administered to pregnant rabbits at doses equivalent to human therapeutic doses, it can increase the chance of early embryonic death. Lamivudine can cross the placenta by passive transport, and serum drug concentrations in newborn animals are similar to those in the mother and umbilical cord.

There is no information on the use of this product in pregnant women, so pregnancy is contraindicated while taking the drug.

Women who become pregnant inadvertently while using lamivudine must consider the possibility of recurrence of hepatitis after discontinuation of lamivudine therapy, and the pros and cons of terminating the pregnancy must be weighed and discussed with the patient and her family.

Breastfeeding : Following oral administration, lamivudine concentrations in breast milk are similar to those in plasma (range 1-8 mg/mL (4.4-34.9 mmol/L), so women taking the drug are advised not to breastfeed their infants.

Children's Use

Data on the use of lamivudine in children are not available in China.

Drug Use in Elderly Patients

See Adult Dosage.

Drug Interactions

The incidence of potential interactions with other drug metabolites is low due to the low drug metabolism and plasma protein binding of this product and its renal clearance primarily as the drug prototype.

Lamivudine is cleared primarily as an active organic cation. Interactions should be considered when used concomitantly with drugs with the same mechanism of excretion, especially when the primary route of clearance of the drug is active renal secretion via the organic cation transport system (e.g., trimethoprim). Some of the other drugs cleared by this mechanism (e.g., ranitidine, cimetidine) have been studied and shown not to interact with lamivudine.

Drugs that are eliminated primarily as reactive organic anions or by glomerular filtration do not interact with lamivudine in a clinically significant manner.

Lamivudine exposure was increased by 40% when administered concomitantly with trimethoprim (160 mg)/sulfamethoxazole (800 mg). However, lamivudine did not affect the pharmacokinetic properties of trimethoprim/sulfamethoxazole. Therefore, no dose adjustment of lamivudine is necessary unless the patient has renal impairment.

When lamivudine was administered concomitantly with zidovudine, a modest increase in zidovudine's Cmax of approximately 28% was observed, but there was no significant change in systemic bioavailability (area under the drug-time curve AUC). Zidovudine did not affect the pharmacokinetic properties of lamivudine.

No pharmacokinetic interactions were observed with concomitant use of lamivudine and alpha-interferon; no clinically significant adverse interactions between lamivudine and commonly used immunosuppressive agents (e.g., cyclosporine A) have been observed. However, this has not been formally studied.

When lamivudine and zalcitabine (zalcitabine) are used concomitantly, lamivudine may inhibit intracellular phosphorylation of the latter. Therefore, it is recommended that these two drugs should not be used at the same time.

Drug Overdose

In the limited information available on acute overdoses in humans, no deaths have occurred and patients have recovered. No specific signs or symptoms were seen after overdose.

While there are no studies on this subject, if an overdose occurs, monitor the patient and give routine supportive care as required. Because lamivudine is cleared by dialysis, continuous hemodialysis may be used for treatment when an overdose occurs and clinical signs or symptoms are present.