Approval date: February 20, 2007
Revision date: June 20, 2013
Date of revision: December 9, 2014
Lamivudine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name.
Lamivudine Tablets
Trade Name
EPIVIRÒ
EPIVIRÒ (3TCÒ)
English Name: Lamivudine Tablets
Hanyu Pinyin: Lamifuding Pian
Ingredients
Ingredients
Chemical Name: (2R,cis)-4-amino-1-[2-hydroxymethyl-5-(1,3-oxathiolanyl)]-1H-pyrimidin-2-one
Chemical structure formula.
Molecular formula: C8H11N3O3S
Molecular weight: 229.26
Properties
This product is a gray diamond-shaped film-coated tablet with “GX EJ7” engraved on one side.
Indications
This product is used in combination with other anti-retroviral drugs for the treatment of human immunodeficiency virus (HIV) infection in adults and children.
Specification
300mg
Dosage]
Initial treatment of patients should be administered by a physician experienced in the treatment of HIV infection.
Epidermolysis bullosa may be taken with food or alone.
To ensure dosing, tablets should be swallowed whole and not crushed. Patients who are unable to swallow tablets may take lamivudine oral solution or may crush the tablet and add it to a small amount of semi-solid food or liquid and take it immediately with food (see [Pharmacokinetics]).
Adults, adolescents and children (weight ≥ 25 kg).
The recommended dose is 300 mg of lamivudine daily. 150 mg twice daily or 300 mg once daily may be taken as an option. (See [Precautions]). 300 mg tablets are indicated for once-daily dosing only.
If a patient changes from twice-daily to once-daily dosing, 300mg tablets should be taken once-daily in the early morning of the day following the 150mg tablets taken twice daily. If the patient is changing from a twice-daily dose to a once-daily dose in the evening, the 150mg tablet may be taken once in the morning followed by a 300mg tablet in the evening. If the patient wishes to change from once-daily to twice-daily dosing, take a sufficient therapeutic dose on the same day and change to 150mg tablets twice daily in the morning of the following day.
Children (3 months of age and weighing <25 kg).
As the exact dose to be administered is not available by prescription, it is recommended to administer the drug according to the weight range. The 150 mg tablet and lamivudine oral solution can be selected depending on the child’s age and weight.
Children under 3 months of age.
Few data are available to suggest a specific recommended dose for this patient population (see [Pharmacokinetics]).
Renal impairment.
Clearance of lamivudine is reduced in patients with moderate to severe renal impairment, resulting in increased plasma concentrations (AUC) of lamivudine. Therefore, the dose of lamivudine should be reduced in patients with creatinine clearance < 50 ml/min, by the method shown in the table below.
Dose recommendations – adults, adolescents and children weighing ³ 25 kg.
Creatinine clearance (ml/min) first dose maintenance dose 30 to < 50150 mg (15 ml) 150 mg (15 ml) once daily 15 to < 30150 mg (15 ml) 100 mg (10 ml) once daily 5 to < 15150 mg (15 ml) 50 mg (5 ml) once daily less than 550 mg (5 ml) 25 mg (2.5 ml) once daily
There is insufficient information on the use of lamivudine in pediatric patients with renal impairment. Given that clearance of lamivudine is approximate in children and adults, reduce the drug dose by the same percentage for pediatric patients with renal impairment.
Dose recommendations – Children ≥ 3 months of age and weighing less than 25 kg.
Creatinine clearance (ml/min) first dose maintenance dose 30 to <504 mg/kg4 mg/kg once daily 15 to <304 mg/kg2.6 mg/kg once daily 5 to <154 mg/kg1.3 mg/kg once daily less than 51.3 mg/kg0.7 mg/kg once daily
Liver damage.
Data from patients with moderate-to-severe hepatic impairment suggest that hepatic insufficiency does not significantly affect the pharmacokinetics of lamivudine. Based on these data, no dose adjustment is necessary in patients with moderate-to-severe hepatic impairment, unless accompanied by impaired renal function.
Adverse reactions]
The following events have been reported during the treatment of HIV disease with lamivudine alone and in combination with other anti-retroviral drugs. Some of these events were uncertain whether they were drug-related or whether they were due to the primary disease process.
Adverse events that are potentially treatment-related are described separately by body system, organ class, and incidence as follows.
The conventional expressions for the classification of adverse reactions are: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), and very rare (<1/10,000).
Hematologic and lymphatic system symptoms
Unusual: neutropenia (occasionally severe), anemia, thrombocytopenia
Very rare/ pure red blood cell aplastic anemia.
Metabolic and nutritional disorders
Common: Hyperlactatemia.
Rare/lactic acidosis (see [Precautions]).
Redistribution/accumulation of body fat (see [Precautions]). This event is influenced by a variety of factors, including co-administration with specific anti-retroviral drugs.
Neurological
Common:Headache, insomnia.
Extremely rare:peripheral neuropathy (but uncertain causal relationship to treatment) or sensory abnormalities.
Respiratory, thoracic and mediastinal disease
Common:cough, nasal symptoms
Gastrointestinal tract
Common/nausea, vomiting, epigastric pain, diarrhea
Rare: elevated serum amylase, pancreatitis has been reported (but causal relationship with treatment is uncertain)
Hepatobiliary system
Uncommon: transient elevation of liver enzymes (AST, ALT).
Rare: hepatitis.
Skin and subcutaneous tissue
Common: rash, hair loss.
Muscle, bone and joint tissues
Common: arthralgia, muscle dysfunction.
Rare: rhabdomyolysis.
Systemic diseases and various reactions at the drug administration site
Common: fatigue, malaise, fever.
Combination antiretroviral therapy may be associated with metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia (see [Precautions]).
HIV-infected patients with severe immunodeficiency are at risk for an enhanced inflammatory response to otherwise asymptomatic or residual opportunistic infections when initiating treatment with antiretroviral drugs (CART) (see [Precautions]).
There have been case reports of osteonecrosis, particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART), occurring with unknown frequency (see [Precautions]).
The safety database supporting once-daily administration of lamivudine in pediatric patients comes from the ARROW trial (COL105677) in which 669 pediatric subjects infected with HIV-1 received once- or twice-daily dosing of abacavir and lamivudine (see [Clinical Trials]). There were no other safety concerns in the pediatric subjects treated with once- or twice-daily dosing compared to adults.
Contraindications
Ipivudine is contraindicated in patients with known hypersensitivity to lamivudine or any of the ingredients in lamivudine preparations.
Precautions]
It is not recommended to treat with EpidavirÒ alone.
Patients should be informed that current anti-retroviral therapy, including EpivirÒ, has not been shown to prevent the risk of HIV transmission through sexual contact or blood-borne contamination. Appropriate prophylaxis should continue to be given.
.
Patients receiving EpidavirÒ or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection and should therefore be closely monitored clinically by a physician experienced in the treatment of HIV-related conditions.
Renal impairment: In patients with moderate to severe renal impairment, lamivudine plasma concentrations (AUC) are elevated due to decreased clearance. Therefore, the dose of the drug should be adjusted (see [Dosage]).
Pancreatitis: Pancreatitis has been reported in patients treated with Epidermolysis bullosa Ò. However, it is unclear whether these cases were due to anti-retroviral therapy or to underlying HIV disease. Once a patient develops clinical signs, symptoms or abnormal laboratory tests during the course of drug administration, the possibility of pancreatitis should be considered and Epidemic VivaÒ should be discontinued immediately.
Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with anti-retroviral nucleoside analogs as monotherapy or in combination (including lamivudine). Most of the above cases were female.
Clinical features suggestive of lactic acidosis include general weakness, anorexia and sudden weight loss of unknown origin, gastrointestinal symptoms and respiratory symptoms (dyspnea and shortness of breath).
Caution should be exercised when taking this product, especially in patients with risk factors for liver disease. Suspension of lamivudine is required in the presence of any clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (including hepatomegaly, steatosis, even in the absence of significant transaminase elevation).
Mitochondrial dysfunction: In vitro and in vivo studies have shown that nucleosides and nucleoside analogs can cause varying degrees of mitochondrial damage. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogs in utero and/or after birth. The major adverse events reported include hematologic abnormalities (anemia, neutropenia), and metabolic abnormalities (hyperlactatemia, hyperlipaseemia). These events are usually transient in nature. Some late onset neurological abnormalities (hypertonia, convulsions, behavioral abnormalities) have been reported. Whether these neurological abnormalities are transient or persistent is unknown. Children exposed in utero to nucleosides and nucleoside analogs (even if HIV negative) should be followed clinically and laboratory, and should be thoroughly examined for the possibility of mitochondrial dysfunction if associated signs and symptoms are present. These findings do not affect current national recommendations regarding the use of antiretroviral therapy in pregnant women to prevent vertical HIV transmission.
Lipids and glucose: Lipid and glucose levels may be elevated during antiretroviral therapy. Disease control and lifestyle changes may be contributing factors. Measurement of lipids and glucose should be considered. Lipid abnormalities should be managed appropriately in the clinical setting.
Patients with co-infection with hepatitis B virus: Clinical trials and post-marketing use of lamivudine have shown evidence of hepatitis recurrence in certain patients with chronic hepatitis B virus (HBV) infection, both clinically and on laboratory tests, once lamivudine is discontinued. This condition may present with more serious adverse outcomes in patients with decompensated liver disease. Regular monitoring of liver function and markers of HBV replication should be considered in patients with co-infection with HBV if they discontinue Epidemic VivaÒ.
Immune Reconstitution Inflammatory Syndrome: HIV-infected patients with severe immunodeficiency can elicit inflammatory responses to otherwise asymptomatic or residual opportunistic infections and lead to severe clinical conditions or worsening of symptoms when treatment with antiretroviral agents (CART) is initiated. Typically these reactions can be observed within the first few weeks or months when ART therapy is initiated. Examples include cytomegalovirus retinitis, systemic and/or focal mycobacterial infections and Yersinia pneumonia (PCP). The occurrence of any inflammatory symptoms must be evaluated immediately and treatment given if necessary. Autoimmune disorders (e.g. Graves’ disease, dermatomyositis and Guillain-Barre syndrome) have been reported in immune reconstitution; however, the timing of the episodes is uncertain and may occur several months after treatment or may sometimes be atypical in presentation.
Liver disease: When lamivudine is used for the treatment of mixed HIV and chronic hepatitis B infection, information about lamivudine for the treatment of chronic hepatitis B is available in the instructions for HerceptinÒ.
There is an elevated risk of serious and potentially fatal hepatic adverse events in patients with chronic hepatitis B or C co-infection who are treated with combination anti-retroviral therapy. If patients with hepatitis B or C are on combination anti-retroviral therapy, please consult the relevant product information for these drugs.
If lamivudine is discontinued in patients with mixed HIV and HBV infection, then periodic liver function checks and monitoring for markers of HBV replication should be considered, as discontinuation of lamivudine may lead to a dramatic worsening of hepatitis.
Patients with pre-existing abnormal liver function (including chronic active hepatitis) have an increased incidence of abnormal liver function during combination anti-retroviral therapy and should be monitored according to routine local standards of care. If there is evidence of worsening liver disease in these patients, treatment interruption or discontinuation must be considered.
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART), and the etiology is generally considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, and high body mass index). Patients should be advised to seek medical attention if they present with arthralgia, joint stiffness, or difficulty with movement.
Special Patient Groups
Children
In clinical trials, children who received lamivudine oral solution in combination with other anti-retroviral oral solutions at any given time had lower rates of virologic suppression, lower lamivudine plasma exposure, and more frequent development of viral resistance than children who received tablets (see Clinical Trials and Pharmacokinetics).
Co-administration of lamivudine oral solution and other ARV oral solutions for the treatment of HIV infection is used only when the therapeutic benefit outweighs the potential risks, including low virologic suppression.
Effects on judgment, driving, or cognitive performance
No studies have been conducted on the effects of lamivudine on driving and mechanical handling.
[For Pregnant and Lactating Women].
Pregnancy.
Studies on animal reproduction have not shown teratogenic effects of lamivudine, and the drug has no effect on fertility in males and females.
The Anti-Retroviral Drug Pregnancy Registry, evaluated lamivudine in 11,000 women during pregnancy and postpartum. Human data obtained from the Anti-Retroviral Drug Pregnancy Registry did not show a higher risk of major birth defects due to lamivudine than the background incidence (see [Clinical Trials]). However, adequate and well-controlled trials in pregnant women have not been conducted, and the safety of lamivudine use during pregnancy has not been established.
Human studies have confirmed the ability of lamivudine to cross the placenta. Lamivudine should be considered during pregnancy only if the benefits outweigh the risks. Although the results of animal studies may not always predict the response in humans, the results of rabbit studies suggest a potential risk of early embryonic death.
Mild transient elevations in serum lactate levels have been reported in neonates and infants exposed in utero and postnatally to nucleoside reverse transcriptase inhibitors (NRTIs), possibly due to mitochondrial dysfunction. The clinical significance of the transient elevation of serum lactate is not known. Delayed development, seizures and other neurological disorders have also been reported very rarely. However, a causal relationship between these events and in utero or postnatal NRTI exposure has not been established. These results do not affect the current recommendations related to the use of ARVs in pregnant women to prevent vertical HIV transmission.
Lactation.
Oral lamivudine is excreted via breast milk, which contains the same concentration of drug as serum. Because both lamivudine and the virus can pass into breast milk, mothers taking EpidavirÒ are advised not to breastfeed their infants. To avoid transmission of HIV
HIV-infected mothers are advised not to breastfeed their infants under any circumstances.
In studies with multiple oral doses of lamivudine 150 mg twice daily (combined with 300 mg zidovudine twice daily) or 300 mg twice daily, lamivudine was secreted into human breast milk at concentrations (0.5 to 8.2 μg/ml) similar to serum concentrations. In other studies with multiple oral doses of 150 mg of lamivudine (combined with 300 mg of zidovudine or diclazideÒ or trixivirÒ), the ratio of lamivudine concentrations in milk to maternal plasma ranged from 0.6 to 3.3. The median serum concentration of lamivudine in infants ranged from 18 to 28 ng/ml, but was not detected in one of these studies (assay sensitivity 7 ng/ml). Intracellular lamivudine triphosphate (the active metabolite of lamivudine) levels were not measured in nursing infants, so the clinical relevance of maternal drug serum concentrations measured in infants is unknown.
Pediatric Use]
See [Dosage].
See [Dosage].
Geriatric Use
See [Dosage] for adult dosing.
Drug Interactions
Due to low metabolism, low plasma protein binding and almost complete renal clearance, lamivudine has little potential to interact with other drugs.
It has been observed that when zidovudine is combined with lamivudine, the Cmax of zidovudine
was moderately elevated (28%) when zidovudine was combined with lamivudine, but there was no significant change in total exposure (AUC) levels. Zidovudine had no effect on the pharmacokinetics of lamivudine (see Pharmacokinetics).
The possibility of interactions between lamivudine and other concomitant drugs should be considered, especially drugs whose primary pathway of clearance is all through the organic cation transport system (e.g., meperidine) for active secretion in the kidney.
Other drugs (e.g. ranitidine, cimetidine) are only partially cleared by this mechanism and no interaction with lamivudine has been shown. Nucleoside analogs (e.g., desoxynivalenosine), like zidovudine, are not cleared by this mechanism and are unlikely to interact with lamivudine.
Coadministration of meperidine/sulfamethoxazole 160 mg/800 mg, in which the meperidine component increases lamivudine exposure by 40%, does not interact with the sulfamethoxazole component. However, it is not necessary to adjust the dosage of lamivudine unless the patient has impaired renal function (see [DOSAGE AND ADMINISTRATION]). Lamivudine has no effect on the pharmacokinetics of methotrexate or sulfamethoxazole. When concomitant use of these drugs is required, the patient should be monitored clinically. Interactions between lamivudine and higher doses of co-trimoxazole in the treatment of Yersinia pneumonia (PCP) and toxoplasmosis have not been studied.
The metabolism of lamivudine does not involve CYP3A and interactions with drugs metabolized by this system (e.g., protease inhibitors) are unlikely.
Until further information is available, it is recommended that lamivudine not be combined with intravenous ganciclovir or phosphonates.
When lamivudine is combined with zalcitabine, lamivudine may inhibit intracellular zalcitabine phosphorylation. Therefore, lamivudine is not recommended for use in combination with zalcitabine.
When lamivudine is combined with emtricitabine, lamivudine may inhibit intracellular phosphorylation of emtricitabine. In addition, the viral resistance mechanism of both lamivudine and emtricitabine is mediated by mutations in the same viral reverse transcriptase locus (M184V); therefore, the efficacy of these drugs may be limited when used in combination. Therefore, the combination of lamivudine with emtricitabine or emtricitabine-containing combinations is not recommended.
Drug overdose]
In acute experimental studies in animals, lamivudine at high doses did not cause toxic reactions in any organ. There are few studies on the consequences of acute overdose of lamivudine in humans. From the data available, patients were able to recover and there were no fatal cases. In the cases of overdose described above, patients did not show specific features and symptoms.
If a patient overdoses, he should be monitored and, if necessary, given conventional supportive therapy. Because lamivudine is dialyzable, hemodialysis may be used in the treatment of drug overdose, although no studies have been conducted in this area.
[Clinical trials].
A randomized, multicenter, controlled study comparing once-daily versus twice-daily dosing regimens of abacavir and lamivudine was conducted in HIV-infected pediatric patients. 1206 pediatric patients aged 3 months to 17 years were enrolled in the ARROW trial (COL105677) and dosed according to the weight-based dosing recommendations of the World Health Organization treatment guidelines (Infants and Children with HIV Infection Anti-Retroviral Therapy, 2006). After 36 weeks of treatment with a regimen containing abacavir and lamivudine twice daily, 669 eligible subjects were randomized to continue treatment with the twice-daily regimen for at least 96 weeks or to switch to the once-daily regimen, respectively. A summary of the results can be found in the following table.
Virologic response based on plasma HIV-1 RNA levels less than 80 copies/ml at weeks 48 and 96 in the Abacavir and Lamivudine Once- and Twice Daily Regimens Randomized Comparison Trial ARROW (observational analysis)
Twice-daily
N (%) Once daily
N (%) Week 0 (after ≥36 weeks of treatment) plasma HIV-1 RNA levels <80 c/mL250/331 (76) 237/335 (71) Risk difference (once daily – twice daily) -4.8% (95% CI -11.5% to +1.9%), p=0.16 Week 48 plasma HIV-1 RNA levels <80 c /mL242/331 (73) 236/330 (72) Risk difference (once-daily-twice-daily) -1.6% (95% CI -8.4% to +5.2%), p=0.65 Week 96 plasma HIV-1 RNA levels <80 c/mL234/326 (72) 230/331 (69) Risk difference (once-daily-twice-daily) -2.3% (95% CI -8.4% to +5.2%), p=0.65 Week 96 plasma HIV-1 RNA levels <80 c/mL234/326 (72) 230/331 (69) Risk difference (once- twice-daily) -2.3% (95% CI -9.3% to +4.7%), p=0.52
Using HIV RNA<80c/mL and all other thresholds (<200c/mL, <400c/mL, <1000c/mL) at week 48 (primary endpoint) and week 96 (secondary endpoint) as indicators, the abacavir/lamivudine once-daily dosing group was not inferior to the twice-daily group based on a prespecified non-inferiority threshold of -12%. dosing group. Subgroup analysis tests of heterogeneity between the once- and twice-daily dosing groups showed no significant effect of sex, age, or viral load at randomization. Conclusions using any of the analysis methods supported non-inferiority.
At randomization to once-daily or twice-daily dosing (week 0), viral load suppression was higher in patients treated with tablets than in those treated with oral solution at any time. These differences were observed in all age-specific study groups, and the difference in suppression rates between tablets and oral solution persisted in the once-daily dosing group until week 96.
Proportion of subjects with plasma HIV RNA<80 copies/mL in the ARROW randomized comparison trial of once- and twice-daily regimens of abacavir and lamivudine: analysis of formulation subgroups
Twice-daily
Plasma HIV-1 RNA <80 c/mL: n/N (%) once daily
Plasma HIV-1 RNA <80 c/mL: n/N (%) Week 0
(after 36 weeks of treatment) Any oral solution dosing regimen at any time 14/26 (54) 15/30 (50) All tablet dosing regimens throughout 236/305 (77) 222/305 (73) 96 weeks Any oral solution dosing regimen at any time 13/26 (50) 17/30 (57) All tablet dosing regimens throughout 221/ 300 (74) 213/301 (71)
Genotypic resistance analysis was performed on samples with plasma HIV-1 RNA>1000 copies/ml. More cases of drug resistance were detected in patients receiving lamivudine oral solution in combination with other anti-retroviral oral solutions compared to those receiving the same dose of tablet administration. This is consistent with the lower rates of antiviral suppression observed in these patients.
The ARV Pregnancy Registry received more than 11,000 reports of fetal survival following lamivudine exposure during pregnancy. Of these, 4,200 were exposed in the first trimester and more than 6,900 in the middle/end of pregnancy, of which 135 and 198 birth defects were reported, respectively. The incidence of defects was 3.2% (95% CI) in patients with pre-gestational exposure (2.6, 3.7%) and 2.8% (2.4, 3.2%) in patients with midterm/end-of-gestation exposure. The background incidence of birth defects among pregnant women in the reference population was 2.7%. Information from the Anti-Retroviral Drug Pregnancy Registry did not show a higher risk of major birth defects due to lamivudine than the background incidence.
Pharmacology and Toxicology]
Pharmacological effects
Lamivudine is a nucleoside analogue with inhibitory effects on HIV and HBV. Lamivudine is metabolized intracellularly to lamivudine 5′-triphosphate, whose primary mode of action is as a chain terminator during viral reverse transcription. The above triphosphate selectively inhibits HIV-1 and HIV-2 replication in vitro, and it also inhibits zidovudine-resistant HIV. In vitro studies have not found antagonistic effects of lamivudine with other anti-retroviral drugs.
HIV-1 resistance to lamivudine is manifested by an M184V mutation in an amino acid adjacent to the active site of the viral reverse transcriptase (RT). This mutation was found in both in vitro assays and in HIV-1-infected patients treated with lamivudine-containing antiviral therapy.The M184V variant exhibited low susceptibility to lamivudine and showed low viral replication capacity in in vitro assays. In vitro experiments have shown that zidovudine-resistant viral isolates will become susceptible to zidovudine again when resistant to lamivudine, but the clinical relevance of this finding has not been determined.
Cross-resistance to M184V reverse transcriptase is limited to anti-retroviral nucleoside inhibitors. Zidovudine and stavudine maintain antiviral activity against lamivudine-resistant HIV-1. Abacavir maintained antiviral activity against lamivudine-resistant HIV-1 containing only the M184V variant, which showed a nearly fourfold reduction in susceptibility to desoxymethyldeoxyinosine and zalcitabine, but the clinical significance of this finding is not known. In vitro susceptibility assays have not been standardized, and results vary depending on methodological factors.
In in vitro assays, lamivudine has demonstrated low toxicity to peripheral blood lymphocytes, lymphocytes and monocyte-macrophage lines established in vitro, and various types of bone marrow progenitor cells.
In clinical trials, coadministration of lamivudine with zidovudine reduced HIV-1 viral load and increased CD4 cell counts. Clinical endpoint data suggest that lamivudine significantly reduces the risk of disease progression and mortality when used in combination with zidovudine or with a zidovudine-containing regimen.
In vitro sensitivity of HIV isolates to lamivudine is reduced in patients who have received lamivudine.
Clinical studies have shown that co-administration of lamivudine with zidovudine in individuals who have not received antiretroviral therapy delays the emergence of zidovudine-resistant isolates.
Lamivudine is widely used in combination therapy with other ARVs of the same type (nucleoside ARVs) or different types (protease inhibitors, non-nucleoside ARVs).
Evidence from clinical trials of pediatric patients receiving lamivudine in combination with other ARVs (abacavir, nevirapine/efavirenz, or zidovudine) suggests that resistance characteristics (including type and frequency of viral mutations) in pediatric patients are similar to those in adults.
In clinical trials, the incidence of viral resistance was more frequent in children receiving lamivudine oral solution in combination with other anti-retroviral oral solutions than in children receiving tablet administration (see [Clinical Trials] and [Pharmacokinetics]).
Multi-drug combination antiviral therapy containing lamivudine has been shown to be effective in both patients on primary anti-retroviral therapy and those carrying the M184V mutant virus.
The relationship between HIV susceptibility to lamivudine in vitro and clinical response to treatment remains to be further investigated.
Toxicological studies
In animal toxicity studies with lamivudine, no vital organ toxicity reactions occurred at high doses. At the highest dose levels, mild effects on hepatic and renal functional parameters (sometimes with reduced liver weight) were seen. Clinically relevant effects noted were decreased red blood cell count and neutropenia.
In bacterial tests, lamivudine was not mutagenic. However, as with many nucleoside analogues, it was shown to have this effect in an in vitro cytogenetic assay and in a mouse lymphoma assay. Lamivudine is not genotoxic in animals at plasma concentrations 40-50 times higher than the expected clinical plasma levels. Since the mutagenic effect of lamivudine in vitro has not been demonstrated in in vivo assays, in general, lamivudine is not considered to pose a risk of genotoxicity in treated patients.
Results of long-term carcinogenicity studies in rats and mice have shown that lamivudine does not have any carcinogenic potential relevant to humans.
[Pharmacokinetics].
Absorption.
Lamivudine is well absorbed via the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is generally 80%-85%. After oral administration, the average time to reach the maximum serum concentration (Cmax) (tmax) is about one hour. At therapeutic doses (i.e., 4 mg/kg/day in 2 divided doses 12 hours apart), Cmax
was 1.5-1.9 mg/ml.
Lamivudine 150mg tablets versus 300mg tablets showed an increase in AUC0-∞, Cmax
and Tmax
were dose-related and bioequivalent in terms of AUC0-∞, Cmax and Tmax. In adults, administration of tablets was equivalent to oral solution in terms of AUC0-∞ and Cmax.
Concomitant administration of lamivudine with food resulted in tmax
prolonged and Cmax
decreased ( by 47%). However, the absorption of lamivudine was not affected ( according to AUC).
Zidovudine exposure increased by 13% and peak plasma concentration increased by 28% when combined with zidovudine. Considering that this is not significant for patient safety, no dose adjustment is required.
Differences in absorption were observed between adults and children.
Distribution.
The mean volume of distribution of lamivudine, as learned from intravenous studies, was 1.3 l/kg. The observed clearance half-life was 5 to 7 hours. The mean systemic clearance of lamivudine was approximately 0.32 l/h/kg, with predominant clearance via the renal organic cation transport system (> 70%). A small fraction (less than 10%) passes through hepatic metabolism.
Lamivudine has linear pharmacokinetics in the therapeutic dose range and binds less to the major plasma protein albumin (<16%-36% to albumin in in vitro studies).
Fewer data show that lamivudine enters the central nervous system and reaches the cerebrospinal fluid (CSF). The ratio of mean CSF to serum lamivudine concentration 2 to 4 hours after oral lamivudine administration is approximately 0.12. The exact amount of lamivudine entering the CNS or the relationship to any clinical effects is not known.
Metabolism.
The active portion of this product, intracellular lamivudine triphosphate, has a longer half-life (16 to 19 hours) than plasma lamivudine half-life (5 to 7 hours). In a clinical study of 60 adult healthy subjects, the pharmacokinetics of intracellular lamivudine triphosphate AUC0-24 and Cmax were equivalent at steady state between 300 mg tablets once daily and 150 mg tablets twice daily.
Lamivudine is cleared primarily as a prototype by renal excretion. Drugs that require metabolism in vivo have little potential to interact with lamivudine because of its small hepatic metabolism (5-10%) and low binding to plasma proteins.
Excretion.
Studies in patients with renal impairment have shown that clearance of lamivudine is affected by renal insufficiency. For patients with creatinine clearance less than 50 ml/min, the recommended dose is described in [Dosage]. Interaction with meperidine, one of the components of cotrimoxazole, increases lamivudine exposure by 40% at therapeutic doses. No dose adjustment is required for this purpose unless the patient has renal impairment (see [Drug Interactions] and [Dosage]). Patients with renal impairment should be cautiously examined for concomitant use of cotrimoxazole and lamivudine.
Pediatric Pharmacokinetics.
Absolute bioavailability of lamivudine (approximately 58%-66% ) is lower and more variable in pediatric patients under 12 years of age. In children, plasma lamivudine AUC and Cmax are higher after coadministration of tablets and other ARVs than after coadministration of oral solutions and other ARVs. Children treated with lamivudine oral solution at the recommended dose had plasma lamivudine exposures in the range of values observed in adults. Children treated with lamivudine tablets at the recommended dose have higher plasma lamivudine exposure than children treated with oral solution because of the higher dose (mg/kg) administered in tablets and the higher bioavailability of the tablets (see [DOSAGE]). Pharmacokinetic studies in children receiving oral solution and tablets have shown that the AUC0-24 after once-daily administration is the same as after twice-daily administration when the total daily dose is the same. Because of these differences, the recommended dose for children no younger than 3 months of age weighing less than 25 kg is 4 mg/kg twice daily. The mean AUC for this dose is approximately 3800-5300ng.h/ml.
Little information is available on the pharmacokinetics in children under 3 months of age. 1-week-old neonates have reduced clearance of oral lamivudine compared to pediatric patients, possibly due to their immature renal function and differences in absorption. Therefore, to achieve the same exposure as in adults and children, the recommended dose for neonates is 4 mg/kg/day. Estimates of glomerular filtration suggest that to achieve exposure approximating that of adults and children, the recommended dose for children 6 weeks of age and older is 8 mg/kg/day.
Pharmacokinetics in pregnancy.
The pharmacokinetics of oral lamivudine in pregnant women in late pregnancy are the same as in nonpregnant adults. Consistent with the passive transport of lamivudine through the placenta in humans, the serum concentration of lamivudine at birth is similar to the maternal and umbilical cord serum concentrations at delivery.
Storage
Store at 30°C or below.
Packaging
In white high-density polyethylene (HDPE) bottle with a cap that is not easily opened by children.
30 tablets/box.
Expiration date
36 months.
Standard
Imported drug registration standard JX20030013
[Approval number
Imported drug registration certificate no.
H20140461
Manufacturer
Production
Production
Enterprise
Industry: Glaxo Wellcome Operations
Production
Production
Location
Address: Priory Street, Ware, Hertfordshire SG12 ODJ, UK (UK)
Package
Packaging
Company
Company: GlaxoSmithKline Pharmaceuticals SA
Package
Packaging
Address
Address: ul.Grunwaldzka 189, Poznan 60-322, Poland.
Office in China: 6th Floor, Metropolitan Headquarters Building, 168 Xizang Middle Road, Shanghai.
Postal code:200001
Telephone number: (86 21) 23019800.
Fax number: (86 21) 23019801
24-hour service hotline: 800-820-3383/400-183-3383
EPIVIRÒ and EPIVIRÒ are registered trademarks of ViiV Healthcare Group, Inc. Copyright © ViiV Health Group, Inc. 2016.