Approval date: February 20, 2007
Revision date: February 2, 2008
November 24, 2010
October 11, 2014
October 14, 2015
October 18, 2016
Year Month Day
Instructions for Zidoramisibifedine Tablets
Please read the instructions carefully and use under the guidance of a physician
Warnings
Hematologic toxic reactions, myopathy, lactic acidosis, exacerbation of hepatitis B
Hematologic Toxicity: One of the components of zidoramibifovudine tablets (zidoramibifudine), zidovudine, can cause hematologic toxic reactions, including neutropenia and anemia, particularly in patients with advanced HIV-1 disease (see [Precautions]).
Myopathy: Long-term use of zidovudine can lead to symptomatic myopathy (see [Precautions]).
Lactic acidosis and severe hepatomegaly: Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogue monotherapy or combination therapy (including zidovudine, lamivudine, and other antiretrovirals). Treatment should be suspended in the presence of clinical or laboratory signs suggestive of lactic acidosis or significant hepatotoxicity (see [Precautions]).
After discontinuation of zidoramiphosgene tablets in patients co-infected with HIV1 and HBV, patients’ liver function should be closely monitored by clinical and laboratory follow-up for at least several months. Give anti-hepatitis B therapy when appropriate (see [Precautions]).
Drug Name]
Generic name: Zidoramisibifedin Tablets
Trade name: Zidovudine
English name: Zidovudine and Lamivudine Tablets
Hanyu Pinyin: Qiduolamishuangfuding Pian
Ingredients
This product is a compound preparation, the composition of each tablet contains 300mg of Zidovudine and 150mg of Lamivudine.
Properties
White or off-white capsule-shaped film-coated scored tablets with “GX FC3” printed on both sides.
Indications
This product is used alone or in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection.
Specification
Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine.
Dosage]
This product can be taken with or without food.
To ensure the integrity of the dose, this product should be swallowed and not crushed. For patients who are unable to swallow, the product may be crushed and added to a small amount of semi-solid or liquid food and taken immediately. (See [Pharmacokinetics])
Adults and adolescents weighing ≥30 kg.
The recommended dose of this product is 1 tablet twice daily for a total daily dose of 600 mg of zidovudine and 300 mg of lamivudine.
Children weighing 21-30 kg.
The recommended dose of this product is half a tablet in the morning and one tablet in the evening.
Children weighing 14-21 kg.
The recommended dose of this product is half a tablet twice daily.
For children weighing less than 14 kg, the dose should be administered in accordance with the prescribed dose of lamivudine oral solution and zidovudine syrup monoformulation.
Before prescribing zidoramipivudine tablets, children should be assessed to see if they can swallow the tablets. If the child is unable to swallow zidoramibifedine tablets, liquid oral dosage forms should be prescribed: lamivudine oral solution and zidovudine syrup monoform.
When it is necessary to discontinue or reduce the dose of one of the active ingredients in this product, lamivudine tablets or oral solution, and zidovudine capsules or syrup monoformulations may be used.
Patient monitoring: Hematologic toxicity may be related to pretreatment bone marrow reserve and dose and duration of therapy. Frequent monitoring of hematologic markers to detect severe anemia or granulocytopenia should be recommended in patients with poor bone marrow reserve, particularly in patients with advanced symptomatic HIV disease (see [Precautions]). In patients experiencing hematologic toxicity, hemoglobin reduction can occur as early as 2-4 weeks, while granulocytopenia usually occurs after 6-8 weeks.
Dose Adjustment: Patients with significant anemia (hemoglobin <7.5 g/dL or reduction >25% from baseline), and/or significant granulocytopenia (granulocyte count <750 cells/ mm3 or reduction >50% from baseline) require dose adjustment until evidence of bone marrow recovery is seen (see [Precautions]). For patients with non-severe anemia or granulocytopenia, a reduction in the daily dose is sufficient. In patients presenting with significant anemia, dose adjustment does not necessarily preclude the need for transfusion. If bone marrow recovery occurs after a dose adjustment, a gradual dose increase may be appropriate depending on hematologic indices and the patient’s degree of tolerance. Because dose adjustments with Zidoramibivudine tablets cannot be implemented, single-agent zidovudine and lamivudine preparations should be used when dose adjustments are required. Physicians should refer to the complete instructions for these drugs.
Geriatric Use
No specific information is available; however, special attention is recommended for this age group due to age-related changes, such as decreased renal function and altered hematological parameters.
Dosage in patients with renal impairment.
Patients with renal impairment have increased concentrations of both lamivudine and zidovudine due to reduced clearance. Therefore, it is necessary to adjust the drug dose and it is recommended to use single-agent formulations of lamivudine and zidovudine in patients with reduced renal function (creatinine clearance £ 50 mL/min) (see [Precautions]).
The maximum plasma concentration of zidovudine will be 50% higher in patients with advanced renal failure compared to healthy subjects. Systemic exposure (as measured by the area under the zidovudine concentration-time curve) is increased by 100%; the half-life is not significantly altered. Accumulation of glucosinolate metabolites occurred mainly in patients with renal failure compared to healthy volunteers, but did not cause toxicity (see Table 1).
Table 1 Pharmacokinetics of zidovudine
Mean pharmacokinetic parameters Zidovudine (AZT) Zidovudine glucosinolates (GAZT) Control
(n=6) Uremic
(n=19) control
(n=6) Uremic syndrome
(n=19) Cmax
(mmol/L) 4.0 ± 0.46.2 ± 0.6*14.9 ± 1.431.6 ± 0.9*** AUC
(mmol.hr/L) 5.2 ± 0.611.7 ± 1.1**23.7 ± 1.9402.9 ± 88.6**t1/2 (hr) 1.0 ± 0.21.4 ± 0.10.9 ± 0.18.0 ± 2.0*Numbers are mean ± standard error.
*p < 0.05, **p < 0.01, ***p < 0.001
Hemodialysis and peritoneal dialysis had no significant effect on the clearance of zidovudine. In a few patients their hemodialysis will be more effective than peritoneal dialysis in clearing glucosinolate metabolites. Intermittent dialysis does not require further dose adjustments than those prescribed with creatinine clearance.
Dosing in patients with hepatic impairment.
Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment due to reduced glucosylation. Dose adjustments may be necessary, but precise recommendations cannot be given at this time. If plasma zidovudine levels cannot be monitored, physicians will need to pay special attention to signs of intolerance and, if appropriate, extend the dosing interval. A single formulation of zidovudine and lamivudine is recommended for patients with severe hepatic impairment (see [Precautions]).
[Adverse Reactions].
Adverse events have been reported with the use of lamivudine and zidovudine for the treatment of HIV disease, either when administered separately or in combination. It is not clear whether these adverse events are related to lamivudine, zidovudine, or other drugs used to treat HIV disease, or to the consequences of the pre-existing disease process itself.
Because this product contains lamivudine and zidovudine, the type and severity of adverse reactions associated with each of these compounds is predictable. There is no evidence of additive toxicity following concomitant use of these two compounds. The conventional formulation for classification of adverse events is as follows.
Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000).
Lamivudine: Hematologic and lymphatic disorders Uncommon: neutropenia, anemia, thrombocytopenia Very rare: pure red blood cell aplasia Metabolic and nutritional symptoms Common: hyperlactatemia Rare: lactic acidosis (see [Precautions]) Neurologic symptoms Common: headache Very rare: sensory abnormalities. Peripheral neuropathy has been reported, but its causal relationship with treatment is uncertain. Gastrointestinal symptoms are common: nausea, vomiting, epigastric pain, diarrhea Rare: pancreatitis, but its causal relationship to treatment is uncertain. Serum amylase is elevated. Hepatobiliary system symptoms uncommon: transient elevation of liver enzymes (AST, ALT) skin and subcutaneous tissue-like symptoms common: rash, baldness musculoskeletal and connective tissue symptoms common: arthralgia, muscle disorders rare: rhabdomyolysis systemic discomfort and various reactions at the site of administration common: fatigue, malaise, fever zidovudine: hematologic and lymphatic system disorders common: anemia (may require blood transfusion), neutropenia Granulocytopenia and leukopenia These events occur at higher doses (1200-1500 mg/day), in advanced stages of HIV (especially if the bone marrow reserve is poor prior to treatment), and especially in patients with CD4 counts less than 100/mm3. Dose reduction or discontinuation of therapy may be necessary (see [Precautions]). The incidence of neutropenia is also increased in patients with low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels at the start of zivudine therapy. Uncommon: thrombocytopenia and allohemocytopenia (with bone marrow dysplasia) Rare: pure red blood cell aplasia Very rare: aplastic anemia Metabolic and nutritional symptoms Common: hyperlactatemia Rare: lactic acidosis (see [Precautions]), loss of appetite Zidovudine treatment is associated with reduced subcutaneous fat (see [Precautions]). Psychiatric symptoms rare: anxiety and depression Neurological symptoms common: headache common: dizziness rare: insomnia, abnormal sensations, drowsiness, loss of mental acuity, spasticity. Cardiac organ symptoms rare: cardiomyopathy respiratory, thoracic and mediastinal symptoms uncommon: dyspnea rare: cough gastrointestinal system symptoms very common: nausea common: vomiting, abdominal pain and diarrhea uncommon: gastrointestinal gas rare: oral mucosal pigmentation, taste disturbances and dyspepsia. Pancreatitis. Hepatobiliary system symptoms common: elevated blood levels of liver enzymes and bilirubin rare: hepatic impairment such as severe hepatomegaly with steatosis skin and subcutaneous tissue-like symptoms uncommon: rash and pruritus rare: nail and skin pigmentation, urticaria, and sweating musculoskeletal and connective tissue symptoms common: myalgia uncommon: myopathy renal and urinary system symptoms rare: urinary frequency genital and breast symptoms rare: male Mammary gland developmentGeneral discomfort and various reactions at the site of administrationCommon: discomfortUnusual: fever, generalized pain and debilityRare: chills, chest pain and flu-like syndrome [Contraindication
This product is contraindicated in patients with known hypersensitivity to lamivudine, zidovudine, or to any of the ingredients in this formulation.
Because zidovudine is contraindicated in patients with neutropenia (<0.75 x 109/L), or anemia (<7.5 g/dL or 4.65 mmol/L), this product is also contraindicated in such patients (see [Precautions])
[Precautions].
This section contains warnings and precautions related to lamivudine and zidovudine. No additional precautions or warnings related to the compounded formulation of Diflucan are provided.
If dose modifications are required, it is recommended to take the monoformulations of lamivudine and zidovudine. In such cases, the physician must refer to the prescribing information for the single-formulation.
Patients must exercise caution if self-administering a combination of medications (see [Interactions]).
Patients should be informed that current antiretroviral therapies, including zidoramipivudine tablets, have not been shown to block the risk of HIV transmission through sexual contact or blood contamination. Therefore, appropriate precautions should be taken.
Patients receiving zidoramipivudine tablets or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore, close clinical observation of HIV-infected patients should be maintained by an experienced physician.
Hematologic Toxic Reactions/Bone Marrow Suppression
One of the components of zidoramibefdin tablets, zidovudine, can cause hematologic toxic reactions, including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Zidoramibifovudine tablets should be used with caution in patients with impaired bone marrow function (granulocyte count less than 1,000 cells/mm3 or hemoglobin less than 9.5 g/dL) (see [Adverse Reactions]).
Frequent monitoring of hematology counts should be recommended for patients with advanced HIV-1 treated with Zidoramibifedine Tablets. For other HIV-1 infected patients, periodic hematology counts are recommended. Treatment may need to be interrupted if anemia or neutropenia occurs.
Myopathy
Long-term use of zidovudine can lead to myopathy and myositis with pathologic changes similar to HIV-1 disease, and therefore these conditions may also occur with zidoramibifovudine tablet therapy.
Lactic acidosis/hepatomegaly with steatosis
Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogue monotherapy or combination therapy (including lamivudine, zidovudine, and other antiretrovirals). The majority of these cases were women. Obesity and long-term use of nucleoside analogues are risk factors. Particular caution should be exercised when administering zidoramiphosgene tablets to patients with known risk factors for liver disease; however, cases have been reported in patients without known risk factors. Treatment with zidoramiphosgene tablets should be withheld in patients presenting with any clinical or laboratory signs suggestive of lactic acidosis with or without hepatitis, including hepatomegaly and steatosis, even in the absence of significantly elevated transaminase levels.
Patients with HIV1 and hepatitis B virus co-infection
Post-treatment hepatitis exacerbation: In clinical trials, non-HIV-infected patients receiving lamivudine for chronic HBV showed clinical and laboratory evidence of hepatitis exacerbation after discontinuation of lamivudine. In addition to the reappearance of hepatitis B virus DNA (HBV DNA), hepatitis exacerbations were detected primarily by elevated serum ALT levels. Although most events are self-limiting, fatal cases have been reported in some cases. Similar events have been reported in post-marketing experience in HIV1 and HBV co-infected patients changing from lamivudine-containing HIV1 regimens to lamivudine-free regimens. The causal relationship between the events and discontinuation of lamivudine therapy is unclear. Patients are closely monitored through clinical and laboratory follow-up after discontinuation of treatment. Current evidence is insufficient to determine whether restarting lamivudine therapy alters the course of post-treatment hepatitis exacerbations.
Important differences between lamivudine-containing products: Zidoramibivudine tablets contain the same active ingredient (lamivudine) as Herceptin (lamivudine) tablets and oral solution, but at a higher level. Herceptin was developed for the treatment of chronic hepatitis B. The safety and efficacy of lamivudine in the treatment of chronic hepatitis B in patients co-infected with HIV1 and HBV has not been established.
Emergence of Lamivudine-Resistant HBV: Lamivudine-resistant HBV has been detected in non-HIV-infected patients receiving lamivudine for chronic hepatitis B and has resulted in a diminished treatment response (see full prescribing information for Herceptin for more information). Mutant strains of hepatitis B virus resistant to lamivudine have been reported in HIV-1 infected patients co-infected with hepatitis B virus who received lamivudine-containing antiretroviral regimens.
Combination with other drugs containing lamivudine, zidovudine and/or emtricitabine
Zidoramipivudine Tablets are a fixed-dose combination of lamivudine and zidovudine. It should not be used in combination with other drugs containing lamivudine or zidovudine, including Ipivir (lamivudine) tablets and oral solution; Heptin tablets and oral solution; Rituxan (zidovudine) tablets, capsules, syrup, and I.V. solution; Covidiaz (abacavir sulfate and lamivudine) tablets; or Trixovir (abacavir sulfate, lamivudine, and zidovudine) tablets; or with other drugs containing emtricitabine, including including ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine), sulforaphane (emtricitabine and tenofovir), or COMPLERA (rilpivirine/emtricitabine/tenofovir).
Combination with interferon- and ribavirin-containing regimens
In vitro studies have shown that ribavirin inhibits the phosphorylation of pyrimidine nucleoside analogs such as lamivudine and zidovudine. Although there is no evidence of pharmacokinetic or pharmacodynamic interactions (e.g., diminished virologic suppression of HIV1/HCV) when ribavirin is combined with lamivudine or zidovudine in HIV1/HCV coinfected patients (see [Pharmacokinetics]), HIV1/HCV coinfected patients receiving concurrent antiretroviral combination therapy (for HIV1), interferon α plus/without ribavirin therapy, hepatic failure (sometimes a fatal event) can occur. Treatment-related toxicities, particularly hepatic decompensation, neutropenia, and anemia, should be monitored closely in patients receiving interferon alpha with or without ribavirin in combination with zidoramibefudine tablets. Zidoramiphosgene tablets should be discontinued when medically appropriate. If clinical toxic reactions, including exacerbation of hepatic decompensation (e.g., Child-Pugh score greater than grade 6), consider reducing the dose of interferon alfa, ribavirin, or both, or discontinuing therapy (see full prescribing information for interferon and ribavirin).
Exacerbation of anemia has been reported in HIV1/HCV co-infected patients treated with ribavirin and zidovudine. Combination of ribavirin with zidovudine is not recommended.
Pancreatitis
Use zidoramiphosgovudine tablets with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Zidoramibivudine Tablets must be discontinued immediately if the patient develops clinical signs, symptoms, or laboratory abnormalities suggestive of possible pancreatitis (see [Adverse Reactions]).
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome has been reported in patients receiving combination antiretroviral therapy, including zidoramibifodine tablets. During the initial phase of combination antiretroviral therapy, the patient’s immune system may develop an inflammatory response due to asymptomatic or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Yersinia pneumonia [often referred to as PCP], or tuberculosis) that must be further evaluated and treated.
Disorders of the autoimmune system have also been reported at the time of immune reconstitution (e.g., Graves’ disease, polymyositis, and Guillain-Barre syndrome); however, the timing of reported episodes is uncertain and may occur several months after treatment.
Fat atrophy
Zidovudine treatment is associated with a reduction in subcutaneous fat. Its incidence and severity are related to the cumulative dose of the drug. This fat loss, seen mainly in the face, extremities and buttocks, may be only partially reversible and may improve after a few months of changing to a zidovudine-free regimen. During treatment with zidovudine and other zidovudine-containing products (Rituxan and Trixovir), patients should be evaluated periodically for signs of lipoatrophy and switched to an alternative treatment regimen if possible if lipoatrophy is suspected.
Lipids and blood glucose
During antiretroviral therapy, patients may have elevated lipid and blood glucose levels. Disease control and lifestyle changes may also be relevant influences in causing such elevations. Monitoring of patients’ lipid and glucose levels should be considered. Where clinically appropriate, dyslipidemia should be controlled.
[For pregnant and lactating women].
Pregnancy
Category C pregnancy.
Summary of Fatal Risks: There are no adequate and well-controlled trials of zidoramibifovudine tablets for use in pregnant women. Clinical trial data confirm that treatment of mothers with zidovudine during pregnancy reduces vertical transmission of HIV to the fetus. Animal reproduction studies using lamivudine and zidovudine have shown increased embryotoxicity and fetal malformations (zidovudine) and increased embryonic deaths (lamivudine). Zidoramipivudine tablets should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.
Antiretroviral Pregnancy Registry Program: An antiretroviral pregnancy registry program has been established to monitor maternal-fetal outcomes in pregnant women using zidoramibifovudine tablets and other antiretroviral drugs. Physicians are encouraged to call 1-800-258-4263 to register relevant patients into the antiretroviral pregnancy program.
The pharmacokinetic profile of lamivudine and zidovudine in pregnant women is similar to that of non-pregnant women. No dose adjustment is required during pregnancy.
In a clinical trial, there was no difference in adverse events that occurred in HIV-1 infected women not receiving treatment versus those receiving zidovudine. It is unclear whether the risk of lamivudine-related adverse events changes among pregnant women compared to other HIV-1-infected individuals.
Zidovudine: A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine in preventing maternal-fetal HIV-1 transmission rates. Zidovudine treatment given during pregnancy reduced maternal-fetal HIV-1 transmission rates by 24.9% in the placebo-treated group and 7.8% in the zidovudine-treated group. Pregnancy-related adverse events did not differ between treatment groups. The incidence of congenital anomalies in newborns delivered by mothers in the zidovudine-treated and placebo-treated groups was similar. The abnormalities found included problems with embryogenesis (before 14 weeks) or were detected by ultrasound before or immediately after initiation of trial drug treatment.
In a phase I clinical trial, the pharmacokinetics of zidovudine were studied in eight women in late pregnancy. No evidence of drug accumulation was found as pregnancy progressed. The pharmacokinetics of zidovudine were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, neonatal plasma concentrations of zidovudine at birth were essentially the same as maternal plasma concentrations at delivery.
Fertility
There are no data to suggest that lamivudine-zidovudine has an effect on reproduction in human females, and zidovudine has no effect on sperm count, morphology, or motility in males.
Breastfeeding
Because of the potential for both HIV-1 transmission and serious adverse reactions in breastfed infants, mothers treated with zidoramipivudine tablets should be advised not to breastfeed.
No studies have been conducted to determine whether zidoramiphosphovudine tablets pass into breast milk, but lactation trials using lamivudine and zidovudine have shown that both drugs pass into human breast milk. Lamivudine concentrations were measurable in milk specimens from 20 mothers who received lamivudine monotherapy (300 mg twice daily) or combination therapy (lamivudine 150 mg twice daily plus zidovudine 300 mg twice daily). In another trial, mean zidovudine concentrations in milk and serum were similar in 13 HIV-1-infected women following a single dose of zidovudine 200 mg.
[Pediatric Use].
See [Dosage].
Geriatric use
See [Dosage].
Drug Interactions
Interactions with other drugs: Because this product contains zidovudine and lamivudine, any identified drug interactions that occur with these drugs alone can occur with the use of this product. Because lamivudine has a limited metabolism, low plasma protein binding and is almost completely cleared by the kidneys, drug-lamivudine interactions are less likely to occur. Similarly, zidovudine has low protein binding, but it is cleared primarily by binding to the liver as an inactive glucosylated metabolite. Because there is limited information on drug interactions with zidoramibefdin tablets, caution should be exercised when combining it with other drugs. The interactions listed below are not exhaustive and represent only those interactions of such drugs that should be treated with caution.
Drug interactions related to lamivudine: The potential for interactions should be considered when other drugs are used concomitantly with this product, especially those whose primary route of clearance is active renal secretion, especially through the cationic system, such as meperidine.
Administration of meperidine, i.e., meperidine/sulfamethoxazole 160 mg/800 mg, causes elevated plasma levels of lamivudine. However, no dose adjustment of lamivudine is necessary unless the patient has pre-existing renal impairment. The effect of higher doses of methotrexate on lamivudine plasma levels has not been studied. Lamivudine has no effect on the pharmacokinetics of meperidine/sulfamethoxazole. Lamivudine should be carefully evaluated when administered to patients with renal impairment.
Sorbitol: Sorbitol solutions (3.2 g, 10.2 g, 13.4 g) combined with a single 300 mg oral lamivudine solution resulted in dose-dependent decreases in lamivudine in adults, with decreases in exposure (AUC∞) of 14%, 32%, and 36%, and decreases in Cmax of lamivudine of 28%, 52%, and 55%, respectively. Long-term use of lamivudine together with sorbitol-containing drugs should be avoided if possible. If long-term coadministration cannot be avoided, more frequent monitoring of HIV-1 viral load should be considered.
In in vitro studies, ciprofloxacin, pentazamidine (pentamidine), and ganciclovir have all reduced the anti-HIV activity of lamivudine. Their clinical significance is not known.
When lamivudine and emtricitabine are used together, lamivudine may inhibit the intracellular phosphorylation of emtricitabine. In addition, the viral resistance mechanism of both lamivudine and emtricitabine is mediated through mutations in the same viral reverse transcriptase gene (M184V); therefore, the efficacy of these drugs may be limited when combined. The combination of lamivudine with emtricitabine or an emtricitabine-containing combination is not recommended.
Zidovudine-related interactions: When zidovudine and lamivudine were applied concomitantly, changes in zidovudine plasma levels were not statistically significant. Zidovudine has no effect on the pharmacokinetics of lamivudine (see [Pharmacokinetics]).
Atovaquone: Zidovudine did not affect the pharmacokinetic parameters of atovaquone. However, pharmacokinetic data show that atovaquone decreases the metabolic rate of zidovudine glucosinolate metabolites (33% increase in steady-state AUC of zidovudine and 19% decrease in peak plasma concentration of glucosinolate metabolites). The combination of zidovudine at 500 or 600 mg/day dosage with atovaquone for 3 weeks for the treatment of acute Yersinia pneumonia is unlikely to result in an increased incidence of adverse reactions due to higher zidovudine plasma concentrations. Care should be taken to monitor patients receiving extended atovaquone therapy.
Clarithromycin: Clarithromycin tablets may reduce the absorption of zidovudine. This can be avoided by spacing zidovudine and clarithromycin at least 2 hours apart.
The risk of adverse reactions to zidovudine may be increased when zidovudine is administered concomitantly with drugs that are nephrotoxic, cytotoxic, or interfere with the number or function of red/white blood cells (e.g., etanercept, sulfamethoxazole and methotrexate, adriamycin, ampicillin, systemic pentazamidine, ganciclovir, amphotericin B, flucytosine, perphenazine, perphenazine, adriamycin, or interferon). If it is necessary to use zidoramiphosphovudine tablets and any of the above drugs in combination, extra care should be taken to monitor renal function and hematological parameters and to reduce the dose of one or more drugs.
When zidovudine and stavudine are administered together, zidovudine may inhibit the intracellular phosphorylation of the latter. Therefore, it is recommended that stavudine not be used in combination with zidovudine.
Propofol reduces the transrenal excretion of zidovudine and, similar to other drugs (e.g., codeine, methadone, morphine, isoproterenol, acetaminophen, aspirin or indomethacin, ketoprofen, naproxen, oxazepam (desoxymethylphenidate), lorazepam (chlorohydroxymethylphenidate), cimetidine, clobetine, aminophenazone) may alter zidovudine by competitively inhibiting glucosylation or directly inhibiting hepatic microsomal metabolism to alter the metabolism of zidovudine (see [Precautions]). The potential for drug interactions should be carefully considered prior to the use of such agents in combination therapy with zidovudine tablets, particularly prior to long-term treatment.
In a placebo-controlled study, the application of acetaminophen in conjunction with treatment with zidovudine, especially after long-term therapy, was associated with an increased incidence of neutropenia. However, the available pharmacokinetic data suggest that acetaminophen does not increase either the plasma levels of zidovudine or its glucosinolate metabolite levels.
Low blood levels of phenytoin have been reported in some patients treated with zidovudine, while high levels were recorded in one patient. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both this product and phenytoin, as many patients with advanced HIV infection suffer from central nervous system conditions that may promote seizure activity.
Certain experimental nucleoside analogs that affect DNA replication antagonize the in vitro anti-HIV activity of zidovudine, so concomitant use of these drugs should be avoided.
Certain drugs, such as meperidine and sulfamethoxazole, aerosolized pentazocine, ethacrynic acid, and acyclovir, may be necessary for the treatment or prevention of opportunistic infections. In controlled trials conducted in cases of advanced HIV infection, no increase in toxicity was detected, probably because of limited exposure to these drugs. However, there is one published report of neurotoxicity (significant drowsiness) associated with concomitant use of zidovudine and acyclovir (see interactions related to lamivudine in [Precautions]).
Drug overdose]
There is no experience with overdose of this product. There is limited information on the consequences of acute overdose of lamivudine or zidovudine in humans. However, no deaths have occurred and all patients recovered. There are no specific signs or symptoms following an overdose.
Treatment.
Patients should be closely monitored for evidence of toxicity (see [Adverse Reactions]) and given the necessary supportive therapy.
Because lamivudine is dialyzable, continuous hemodialysis may be used in the event of an overdose, although this has not been studied. Hemodialysis and peritoneal dialysis have negligible effect on the clearance of zidovudine only. The major metabolite is GAZT, which is cleared more efficiently by hemodialysis than by peritoneal dialysis. For more detailed information, physicians can refer to the respective instructions for these drugs.
[Clinical Trials].
Clinical endpoint studies.
Information on clinical endpoints from a prospective study showed that lamivudine in combination with zidovudine or in combination with zidovudine-containing therapy significantly reduced disease progression and mortality.
NUCB3007 (CAESAR), a multicenter, double-blind, placebo-controlled study of current therapies [zidovudine (AZT) alone (62% of patients), or zidovudine combined with dehydroxymethyldeoxyinosine (ddl), or zalcitabine (DDC) (38% of patients)] in combination with lamivudine, or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor A comparison was performed, with randomized groups in a 1:2:1 ratio. A total of 1840 HIV-infected adult patients with CD4 cell counts of 25-250 (median 126) cells/mm3 at baseline were enrolled in the study: median age was 36 years, 87% were male, 83% were treatment-experienced nucleoside analogues, and 17% were untreated. The median duration of therapy in each group was 327 days for current therapy*, 360 days for lamivudine plus current therapy*, and 360 days for lamivudine plus NNRTI** plus current therapy*. The results are shown in Table 2.
Table 2 Number of patients with at least one HIV disease progression event or death (%)
Endpoint
Current therapy*
(n = 471)
Lamivudine plus
Current therapy*
(n = 907) Lamivudine plus an NNRTI** plus
Current therapy* (n = 462)
(n = 462) HIV progression or death 95 (20%) 86 (9%) †42 (9%) death 28 (6%) 23 (3%) ‡14 (3%) *Current therapy = AZT (200 mg three times daily or 250 mg twice daily) monotherapy, AZT + ddl (250 mg twice daily) or AZT + DDC (0.75 mg three times daily).
**An investigational non-nucleoside reverse transcriptase inhibitor that is not yet approved in Australia.
†Lamivudine + current therapy versus single current therapy p<0.0001.
‡Lamivudine + current therapy compared with single current therapy p = 0.0007.
These data showed that patients receiving the combination of lamivudine and zidovudine-containing therapy had a significant reduction (p<0.0001) in progression to a new AIDS event or death at the combined endpoint compared with patients treated with zidovudine-containing therapy alone. The risk ratio (HR) was 0.427 (95% confidence limit 0.318-0.572), or a 57% reduction in risk. In addition, these data also showed that receiving the combination of lamivudine and zidovudine-containing therapy resulted in a significant reduction in death from any cause compared with zidovudine monotherapy (p=0.0007); HR=0.399 (95% confidence limit 0.230-0.963) or a 60% reduction in risk.
ACTG320 was a randomized, double-blind, placebo-controlled study. The study compared indinavir, zidovudine (or stavudine), and lamivudine combined with two-drug treatment with zidovudine (or stavudine) and lamivudine in HIV-infected patients with CD4 counts of £200 cells/mm3. Patients had received ³3 months of zidovudine in the past and had not been previously treated with protease inhibitors. A total of 1156 patients were included in the study. The median duration of follow-up was 38 weeks. During this study period, 96 new AIDS-limited events or deaths occurred, 63 (11%) in the zidovudine/lamivudine group and 33 (6%) in the zidovudine/lamivudine/indinavir group (risk ratio estimated at 0.50). There were 13 (6%) deaths in the zidovudine/lamivudine group and 5 (2%) deaths in the zidovudine/lamivudine/indinavir group (risk ratio of 0.37). Both results were statistically significant.
Alternate endpoint studies in adults.
The indication for zidoramipivudine tablets was based on the analysis of several surrogate endpoints in a clinical study of the combination of lamivudine 150 mg twice daily and zidovudine 200 mg three times daily. The study population was patients who had or had not received antiretroviral therapy in the past.
The study protocols are shown in Table 3. all were randomized, double-blind, multicenter studies. Patient characteristics at baseline are shown in Table 4.
No clinical study results were available for lamivudine 150 mg combined with zidovudine 300 mg twice daily. The dosing regimen of zidovudine 300 mg twice daily in zidoramisibovudine tablets was based on extrapolation of dosing regimens from other clinical studies.
Table 3 Summary Results of Pivotal Efficacy Studies in Adults Summary 0-24 Weeks 0-52 Weeks Study Design – Pivotal Studies in Adults Mean Time Weighted Change at 52 Weeks
Change from Baseline Report Number
(Protocol) Study Design
Patients treated with dose randomized grouping of number of cases regimen CD4Log10 HIV RNACD4Log10
HIV RNAUCR/95/002DB, MCLAM 300mg bd8724 weeks DB24-0.59-11-0.32 (NUCA3001) no prior ZDVZDV 200mg tds93DB continued 17-0.31-53-0.14 CD4 200-500ZDV + LAM 150mg92 55- 1.1261-0.80 ZDV + LAM 300mg94 45-1.1560-1.04 UCR/95/003DB, MCZDV + DDC 0.75mg8624 week DB-2-0.6616-0.50 (NUCA3002) used ZDVZDV + LAM 150mg84DB continued 38-0.8035 -0.48 CD4 100-300ZDV + LAM 300mg84 39-0.9127-0.55 GIO/94/003DB, MCZDV 200mg tds6424 weeks DB18-0.57 (NUCB3001) not used ZDVZDV + LAM 300mg65OL continued 75-1.33 CD4 100 -400 GIO/94/005DB, MCZDV 200mg tds7324 weeks DB-18-0.07 (NUCB3002) Had ZDVZDV + LAM 150mg75OL continued 38-0.96 CD4 100-400ZDV + LAM 300mg75 32-0.77 Zidovudine was administered in all studies at 200 mg administered three times daily. Lamivudine was administered twice daily in all studies.
Note: DB-double-blind; MC-multicenter; OL-open
Table 4 Characteristics of randomly assigned patients in the pivotal studies
NUCA3001NUCA3002NUCB3001NUCB3002Number of patients 366254129223 Age (median) 34373336 Asymptomatic HIV infection 80% 58% 64% 53% Past receipt of antiretroviral
Duration of therapy (months)<124<123 Baseline CD4 cells/mm3200-500100-300100-400100-400 (median) (352) (211) (260) ( 241) After 24 weeks: in patients who had not received zidovudine, the combination of lamivudine and zidovudine caused a significant increase in absolute CD4 cell counts (p<0.001), as well as causing a decrease in log10 HIV-RNA associated with zidovudine monotherapy (600 mg daily) or lamivudine monotherapy (600 mg daily). Similarly, in patients previously treated with zidovudine, the combination of lamivudine and zidovudine caused higher improvements in CD4 cell counts than either zidovudine monotherapy (600 mg daily) or zidovudine in combination with zalcitabine (600 mg + 0.75 mg daily), as well as causing a substantially more significant reduction in log10 HIV -RNA reduction. A meta-analysis of four pivotal trials showed that the combination of lamivudine and zidovudine slowed HIV disease progression compared to the “control” group (all other treatment groups).
In the North American studies (NUCA3001 and NUCA3002), patients were allowed to remain fully blinded until the last patient completed a 24-week evaluation. Analysis of the subgroup of patients who received at least 52 weeks of treatment showed benefit in terms of both CD4 cell count and viral load compared to receiving zidovudine alone during this period (p<0.001). results for CD4 cell count and log10 HIV-RNA are shown in Figure 1.
Figure 1 on patients who had not received and had received zidovudine in
Results of the North American study on the effect of the main substitution parameters Patients who had not received zidovudine: NUCA3001 Patients who had received zidovudine: NUCA3002 Mean change in absolute CD4 cell count from baseline Mean change in absolute CD4 cell count from baseline Mean change in HIV-RNA from baseline Mean change in HIV-RNA from baseline Change in [Pharmacology and Toxicology
Pharmacological effects
Mechanism of action
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). 3TC-TP’s primary mechanism of action is inhibition of reverse transcriptase (RT) by causing suspension of DNA strand synthesis after embedding in a nucleotide analogue.
Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite zidovudine triphosphate (ZDV-TP).The primary mechanism of action of ZDV-TP is to inhibit RT by causing the termination of DNA strand synthesis after embedding in a nucleotide analogue.
Antiviral activity
Lamivudine plus zidovudine: In HIV-1-infected MT-4 cells, the combination of lamivudine and different ratios of zidovudine had no antagonistic effect.
Lamivudine: The antiviral activity of lamivudine against HIV-1 was evaluated in a large number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMC) using standard drug sensitivity assays. EC50 values ranged from 0.003 to 15 μM (1 μM = 0.23 μg/mL). For HIV-1 evolutionary branches A to G and O group viruses (n = 3, except n = 2 for evolutionary branch B), the median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60nM), 30nM (range: 20~70nM), 30nM (range: 3~70nM) and 30nM (range: 20~90nM). EC50 values in PBMC against HIV-2 isolates (n=4) ranged from 0.003 μM to 0.120 μM. In MT-4 cells, ribavirin (50 μM), used for the treatment of chronic HCV infection, reduced the anti-HIV-1 activity of lamivudine by 3.5-fold.
Zidovudine: The antiviral activity of zidovudine against HIV-1 was evaluated in a large number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine ranged from 0.01 to 0.49 μM (1 μM = 0.27 μg/mL) and 0.1 to 9 μM, respectively. for HIV-1 in primed subjects without amino acid substitutions associated with resistance, Virco (n=92 baseline samples) gave a median EC 50 value of 0.011 μM (range: 0.005 to 0.110 μM), while Monogram Biosciences (n=135 baseline samples) gave a median EC 50 value of 0.0017 μM (range: 0.006 to 0.0340 μM). The EC 50 values of zidovudine for different HIV-1 evolutionary branches (A~G) ranged from 0.00018 μM to 0.02 μM, while the EC 50 values for HIV-2 isolates ranged from 0.00049 μM to 0.004 μM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell cultures.
Neither lamivudine nor zidovudine antagonized the anti-HIV drugs tested, with the exception of stavudine, whose antagonistic relationship with zidovudine has been confirmed in cell culture.
Drug resistance
In subjects receiving lamivudine monotherapy or lamivudine plus zidovudine combination therapy, the majority of HIV-1 isolates from the subjects were phenotypically and genotypically resistant to lamivudine within 12 weeks.
HIV-1 strains resistant to lamivudine and zidovudine have been isolated from subjects after long-term lamivudine/zidovudine treatment. Dual resistance requires the presence of multiple amino acid substitutions, the most important of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance can occur are unknown.
Lamivudine: Lamivudine-resistant HIV-1 isolates have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell cultures and recovered from subjects treated with lamivudine showed that the resistance was due to a specific amino acid substitution at codon 184 by HIV-1 reverse transcriptase changing methionine to valine or isoleucine (M184V/I).
Zidovudine: HIV-1 isolates with reduced susceptibility to zidovudine were selected in cell culture and also recovered from subjects treated with zidovudine. Genotypic analysis of isolates selected in cell cultures and recovered from subjects treated with zidovudine showed that thymidine analogue mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y or F, K219E/ R/ H/ Q/ N) in HIV-1 RT resulted in zidovudine resistance. Usually, the more substitutions the higher the level of resistance.
In some subjects carrying zidovudine-resistant virus at baseline, phenotypic susceptibility to zidovudine was restored after 12 weeks of treatment with lamivudine and zidovudine.
Cross-resistance
Cross-resistance was observed in nucleoside reverse transcriptase inhibitors (NRTI). Cross-resistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine monotherapy or lamivudine in combination with zidovudine, isolates showed substitutions at codon 184, which resulted in resistance to lamivudine.
The reverse transcriptase thymidine analogue mutation (TAM) substitution caused by zidovudine can lead to cross-resistance to abacavir, dehydroinositide, stavudine, and tenofovir.
Toxicological studies
Genotoxicity
Lamivudine: Lamivudine is mutagenic in the TK gene mutation assay in L5178Y mouse lymphoma cells and causes chromosome breakage in the human lymphocyte chromosome aberration assay. Lamivudine showed negative results in Ames test, in vitro cell transformation test, rat micronucleus test, rat bone marrow cytogenetics test and rat liver programmed in vitro DNA synthesis test.
Zidovudine: Zidovudine L5178Y mouse lymphoma cell TK gene mutation assay, in vitro cell transformation assay, in vitro human lymphocyte genetics assay, and repeatedly administered mouse and rat micronucleus assays yielded positive results. Cytogenetic assay results were negative in rats given a single dose.
Reproductive toxicity
Lamivudine.
Lamivudine 4000 mg/kg/day [approximately 42 times (male) or 63 times (female) the Cmax of the human dose of 300 mg] did not show effects on fertility in male or female rats.
Lamivudine was administered orally to pregnant rats and rabbits during the organogenesis phase at doses of 90, 600, and 4000 mg/kg/day from day 7 to day 16 of gestation in rats and 90, 300, and 1000 mg/kg/day and 15, 40, and 90 mg/kg/day from day 8 to day 20 of gestation in rabbits). No teratogenic effects were seen with lamivudine at plasma concentrations Cmax higher than approximately 35 times the recommended human dose exposure in rats and rabbits. Early embryonic death was observed in rabbits at systemic exposure AUCs similar to the recommended human systemic dose, but no such phenomenon was observed in rats at plasma concentrations Cmax higher than 35 times the recommended human dose exposure. Tests in pregnant rats have shown that lamivudine passes through the placenta into the fetus.
In a fertility/perinatal developmental toxicity test in rats, maternal rats were given lamivudine 180, 900, and 4000 mg/kg/day orally from pre-mating to postnatal day 20, and no effects on offspring development (including fertility and reproductive function) were observed.
Zidovudine.
Zidovudine was given orally to male and female rats at 450 mg/kg/day [approximately 7 times the recommended adult dose (300 mg twice daily) based on body surface area], and no effect on fertility was seen based on conception rates.
Increased embryonic uptake was seen in rats given zidovudine 50, 150, and 450 mg/kg/day continuously from 26 days prior to mating through gestation until postpartum day 21 at an exposure AUC approximately 33 times the recommended human dose, but in the rat embryo-fetal development toxicity test, zidovudine 125, 250, and 500 mg/kg/day were given orally on days 6-15 of gestation at No embryonic uptake was observed at an exposure AUC of approximately 117 times the recommended human dose. In the rabbit embryo-fetal developmental toxicity test, zidovudine was administered orally at 75, 150, and 500 mg/kg/day on days 6 to 18 of gestation, with increased embryonic uptake seen at 500 mg/kg/day (exposure AUC approximately 108 times the recommended human dose); no embryonic uptake was seen at 150 mg/kg/day (exposure AUC approximately 23 times the recommended human dose). No teratogenic effects were observed in the above rat and rabbit embryo-fetal developmental toxicity assays. In another reproductive toxicity test, zidovudine was administered to rats at 3000 mg/kg/day on days 6-15 of gestation, and significant maternal toxicity and increased fetal malformations were seen at an exposure (based on AUC) of approximately 300 times the recommended human dose, but no teratogenic effects were seen at 600 mg/kg/day.
Carcinogenicity
Lamivudine: Results of long-term carcinogenicity tests in rats and mice showed that lamivudine did not show carcinogenicity at exposures up to 10 times the human clinical exposure (mice) and 58 times the human clinical exposure (rats).
Zidovudine: Three doses of zidovudine were given orally to mice and rats (60 males and females in each group). The initial single daily doses were 30, 60 , 120 mg/kg/day in mice and 8, 220, 600 mg/kg/day in rats. Due to treatment-related anemia, the dose was reduced to 20, 30, and 40 mg/kg/day after day 90 in mice, while in rats, the high dose was reduced only to 450 mg/kg/day on day 91, and then to 300 mg/kg/day on day 279.
In mice, seven late-appearing (after 19 months) vaginal tumors (five non-metastatic squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) appeared in the highest dose group; one late-appearing vaginal squamous cell papilloma appeared in the mid-dose animals; no vaginal tumors were detected at the lowest dose. In rats, two late-appearing (after 20 months) non-metastatic vaginal squamous cell carcinomas appeared in the highest dose group; no vaginal tumors were found in the low or medium dose groups. No other drug-associated tumors were observed in either sex in either species.
The doses that produced tumors in mice and rats, extrapolated from drug exposure (in terms of AUC), were approximately 3 (mice) and 24 (rats) times the estimated exposure of the recommended human therapeutic dose (100 mg every 4 hours).
The predictiveness of the rodent carcinogenicity test results for humans is not known.
[Pharmacokinetics].
Absorption.
Lamivudine and zidovudine are well absorbed in the intestinal tract. Under normal conditions, the oral bioavailability of adult lamivudine is 80-85%, while that of zidovudine is 60-70%.
A bioequivalence study in healthy volunteers compared the effects of zidoramipivudine tablets with lamivudine (3TC) 150 mg tablets and zidovudine (Retrovir) 300 mg tablets.
In fasting studies, zidoramibifovudine tablets were bioequivalent in combination with lamivudine 150 mg and zidovudine 300 mg tablets. The Cmax (95% confidence limit) was 1.5 mg/mL (1.3-1.8) for lamivudine and 1.8 mg/mL (1.5-2.2) for zidovudine after administration of zidoramibifovudine tablets. The median tmax (range) for lamivudine and zidovudine was 0.75 h (0.50-2.00) and 0.50 h (0.25-2.00), respectively. The extent of lamivudine and zidovudine absorption (AUC0-¥) and half-life estimates were similar for both lamivudine and zidovudine after administration of zidoramibifedine tablets with food compared to fasting study subjects.
However, the rate of absorption was reduced for both drugs. The mean Cmax of lamivudine was 85% of the fasting state, while the median tmax increased from 0.75 to 1.5 hours. The mean Cmax of zidovudine was 55% of the fasted state, while the median tmax increased from 0.5 to 1.0 hours.
Crushing the product and taking it with a small amount of semi-solid or liquid food does not affect the quality of the drug and does not alter the clinical effect as a result. This conclusion is based on the biochemical and pharmacokinetic characteristics of the active ingredient and the dissolution behavior of lamivudine-zidovudine combination tablets in water in vitro, and assumes that the patient takes the product immediately after crushing and 100% transfer.
Pharmacokinetics in special patient populations.
Limited information is available on the pharmacokinetics of zidovudine in patients with renal impairment or hepatic impairment. Dose adjustment of zidovudine is required in patients with advanced renal failure and severe hepatic impairment. The pharmacokinetics of zidovudine in pregnant women are also limited. No specific information is available on the pharmacokinetics of zidovudine in elderly patients.
A single-dose pharmacokinetic study of lamivudine showed a linear relationship between lamivudine clearance and renal function in HIV-infected patients (n=16) with normal, moderately impaired renal function (creatinine clearance <30 mL/min but >10 mL/min) and end-stage renal impairment (creatinine clearance <10 mL/min).
Because adjustment of the dose of lamivudine is required in patients with renal impairment and adjustment of the dose of zidovudine is required in patients with advanced renal failure or severe hepatic impairment, it is recommended that compounded formulations, such as zidoramisibovudine tablets, not be used in such patients (see [Precautions]).
Elderly
The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Pediatric Patients
The pharmacokinetic profile of zidovudine in children older than 5-6 months is similar to that of adults. Zidovudine was rapidly absorbed from the gastrointestinal tract at all doses studied in adults and children, with bioavailability ranging from 60% to 74%, with a mean value of 65%. The mean steady-state peak plasma concentrations (Cssmax) were 4.45µM (1.19µg/ml) and 7.7µM (2.06µg/ml) after administration of zidovudine oral solution at 120mg/m2 and 180mg/m2 body surface area, respectively. The systemic exposure of children administered at 180 mg/m2 body surface area for four doses a day (24-hour AUC 40.0hr µM or 10.7hr µg/ml) was consistent with the systemic exposure of adults at 200 mg for six doses a day (40.7hr µM or 10.9hr µg/ml).
The plasma pharmacokinetics of zidovudine were evaluated in six HIV-infected pediatric patients aged 2-13 years who were administered zidovudine at 120 mg/m2 three times a day, followed by an adjustment to twice-a-day dosing at 180 mg/m2. Plasma systemic exposure (daily AUC and Cmax) in the twice-a-day dosing regimen was comparable to that of the three-times-a-day dosing regimen.
Overall, the pharmacokinetics of lamivudine in pediatric patients were similar to those in adults. However, absolute bioavailability was decreased by approximately 55-65% in pediatric patients younger than 12 years of age. In addition, systemic clearance values were greater in younger pediatric patients and gradually decreased with increasing age, reaching adult clearance at approximately 12 years of age. In view of these differences, the recommended dose of lamivudine in pediatric patients (from 3 months of age to 12 years of age, approximately 6 kg to 40 kg) is 8 mg/kg/day.
The mean area under the drug-time curve (AUC0-12) obtained for the above doses ranges from 3,800 to 5,300 ng.h/ml. The results of the latest study suggest that exposure in children aged 2 to 6 years may be reduced by about 30% relative to other age groups. Additional data to support this conclusion are being collected further. However, for the data available to date, the effectiveness of lamivudine is not diminished in this age group.
Distribution.
Studies of intravenous administration have shown that the mean apparent volume of distribution of lamivudine is 1.3 L/kg. binding to plasma proteins is limited. The plasma protein binding of zidovudine ranged from 34% to 48%.
Limited data suggest that the penetration of lamivudine into the central nervous system is relatively low. The mean cerebrospinal fluid/serum concentration ratios of lamivudine and zidovudine after 2-4 hours of administration alone are approximately 0.12 and 0.5, respectively.
Metabolism.
Lamivudine has a low potential for adverse drug interactions because of limited metabolism (hepatic metabolism <10%), limited binding to plasma proteins, and almost complete renal clearance. Interaction with meperidine (i.e., one of the components of compounded sulfamethoxazole) caused a 40% increase in lamivudine exposure after 5 days of administration of meperidine 160 mg/sulfamethoxazole 800 mg once daily. The effect of high doses of meperidine on lamivudine plasma levels has not been studied.
Zidovudine is rapidly metabolized by first-pass effect to 3′-azido-3′-deoxy-5′-O-E-D-glucopyranose furosemide thymidine (GAZT), which has a clearance half-life of 1 hour (range 0.61 to 1.73 hours). Following oral administration, urinary recoveries of zidovudine and GAZT were 14% and 74% of the administered dose, respectively, while the overall urinary recovery averaged 90% (range 63% to 95%), thus indicating a high degree of absorption.
Limited data demonstrate that 3′-amino-3′-deoxythymidine (AMT) is a metabolite of zidovudine after intravenous and oral administration. A small in vitro study showed that AMT reduced the growth of hematopoietic progenitor cells; however, its clinical significance is not known.
Excretion.
The mean terminal clearance half-life of lamivudine is 5 to 7 hours, while mean systemic clearance is approximately 0.32 L/h/kg, with predominant renal clearance (>70%) via active renal tubular secretion and only a small proportion (<10%) via hepatic metabolism.
Studies in patients with renal impairment have shown that lamivudine clearance is influenced by renal dysfunction. For patients with creatinine clearance £50 ml/min, a dose reduction is required (see [Dosage] for details).
The mean terminal clearance half-life of zidovudine is approximately 1 hour, and the transrenal clearance is estimated to be 0.34 L/h/kg, indicating that clearance is primarily by glomerular filtration and active tubular secretion. There are increased concentrations of zidovudine in patients with end-stage renal failure.
Limited data indicate that zidovudine crosses the placenta and can be present in amniotic fluid and fetal blood; zidovudine is also detected in semen. In rats and rabbits, lamivudine can cross the placenta.
Storage】Store at 30°C or below.
Package】Packaged in aluminum-plastic blister, 60 tablets/box
Expiration date】24 months
Standard】Imported drug registration standard JX20150255
Approval number】Imported drug registration certificate No. H20150546
Manufacturer
Manufacturer’s name: GlaxoSmithKline Pharmaceuticals SA
Production Address: ul. Grunwaldzka 189, 60-322 Poznan, Poland (Poland)
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