Zidovudine and Lamivudine interacts in the following cases:
Patients with a creatinine clearance between 30 and 49 mL/min receiving lamivudine/zidovudine may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing lamivudine/zidovudine fixed-dose combination to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudinerelated adverse events (such as gastro-intestinal and hepatic disorders) may occur.
Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive lamivudine/zidovudine should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with lamivudine/zidovudine. Lamivudine/zidovudine combination should be discontinued and the individual components should be used to construct the treatment regimen.
Lamivudine and zidovudine concentrations are increased in patients with renal impairment due to decreased clearance. Therefore as dosage adjustment of these may be necessary it is recommended that separate preparations of lamivudine and zidovudine be administered to patients with severe renal impairment (creatinine clearance ≤30 mL/min). Physicians should refer to the individual prescribing information for these medicinal products.
Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. However, as dosage adjustments for zidovudine may be necessary, it is recommended that separate preparations of lamivudine and zidovudine be administered to patients with severe hepatic impairment. Physicians should refer to the individual prescribing information for these medicinal products.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV. A large amount of data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomes from first trimester exposure each, of which over 2000 outcomes involved exposure to both lamivudine and zidovudine). The malformative risk is unlikely in humans based on the mentioned large amount of data.
The active ingredients of zidovudine/lamivudine may inhibit cellular DNA replication and zidovudine has been shown to be transplacental carcinogen in one animal study. The clinical relevance of these findings is unknown.
For patients co-infected with hepatitis who are being treated with lamivudine containing medicinal products such as zidovudine/lamivudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.
Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues.
Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in serum.
Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.
After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.
It is recommended that mothers infected by HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Neither zidovudine nor lamivudine have shown evidence of impairment of fertility in studies in male and female rats. There are no data on their affect on human female fertility. In men zidovudine has not been shown to affect sperm count, morphology or motility.
No studies on the effects on the ability to drive and use machines have been performed.
Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudine separately or in combination. For many of these events, it is unclear whether they are related to lamivudine, zidovudine, the wide range of medicinal products used in the management of HIV disease, or as a result of the underlying disease process.
The type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of added toxicity following concurrent administration of the two compounds.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine.
Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving lamivudine/zidovudine should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with lamivudine/zidovudine should not be continued.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.
The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare: Pure red cell aplasia
Very Rare: Lactic acidosis
Common: Headache, insomnia
Very rare: Peripheral neuropathy (or paraesthesiae)
Common: Cough, nasal symptoms
Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare: Pancreatitis, rises in serum amylase
Uncommon: Transient rises in liver enzymes (AST, ALT)
Rare: Hepatitis
Common: Rash, alopecia
Rare: Angioedema
Common: Arthralgia, muscle disorders
Rare: Rhabdomyolysis
Common: Fatigue, malaise, fever
The adverse reactions profile appears similar for adults and adolescents. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm³.
The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy.
The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Common: Anaemia, neutropenia and leucopenia
Uncommon: Thrombocyopenia and pancytopenia (with marrow hypoplasia)
Rare: Pure red cell aplasia
Very rare: Aplastic anaemia
Rare: Lactic acidosis in the absence of hypoxaemia, anorexia
Rare: Anxiety and depression
Very common: Headache
Common: Dizziness
Rare: Insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions
Rare: Cardiomyopathy
Uncommon: Dyspnoea
Rare: Cough
Very common: Nausea
Common: Vomiting, abdominal pain and diarrhoea
Uncommon: Flatulence
Rare: Oral mucosa pigmentation, taste perversion and dyspepsia. Pancreatitis
Common: Raised blood levels of liver enzymes and bilirubin
Rare: Liver disorders such as severe hepatomegaly with steatosis
Uncommon: Rash and pruritus
Rare: Nail and skin pigmentation, urticaria and sweating
Common: Myalgia
Uncommon: Myopathy
Rare: Urinary frequency
Rare: Gynaecomastia
Common: Malaise
Uncommon: Fever, generalised pain and asthenia
Rare: Chills, chest pain and influenza-like syndrome
The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse events consistently decreases over time during the first few weeks of therapy with zidovudine.
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