Duovir

Lamivudine / Zidovudine

Film-coated tablets

Oval biconvex film-coated tablets debossed with ‘DVR’ on one side.

1 tablet contains:
Active substance: lamivudine 150 mg, zidovudine 300 mg;
Auxiliary substances: microcrystalline cellulose, colloidal anhydrous silicon dioxide, starch sodium glycolate, magnesium stearate;
Coating composition: hypromellose, titanium dioxide (E171), talc, propylene glycol.

Antivirals for systemic use. Combinations of antivirals for the treatment of HIV infection.

J05AR01

Pharmacodynamics

Mechanism of action
Lamivudine and zidovudine are nucleoside analogues which have activity against HIV. Additionally, lamivudine has activity against hepatitis B virus (HBV). Both medicinal products are metabolised intracellularly to their active moieties, lamivudine 5′-triphosphate (TP) and zidovudine 5′-TP respectively. Their main modes of action are as chain terminators of viral reverse transcription. Lamivudine-TP and zidovudine-TP have selective inhibitory activity against HIV-1 and HIV-2 replication in vitro; lamivudine is also active against zidovudine-resistant clinical isolates of HIV. Lamivudine in combination with zidovudine has synergistic activity against HIV, against clinical isolates in cell culture.

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings has not been defined.

In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible nucleoside analogue reverse-transcriptase inhibitors (NRTI’s) should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available.

Cross-resistance conferred by the M184V mutation in the HIV reverse transcriptase is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardized and results may vary according to methodological factors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro. Resistance to thymidine analogues (of which zidovudine is one) is well characterized and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other nucleosides, allowing for the subsequent use of any of the other approved NRTIs.

Two patterns of multi-drug resistance mutations, the first characterized by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to zidovudine as well as to the other approved NRTIs. Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options.

Clinical Experience
In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and increase CD4 cell count. Clinical data indicate that lamivudine in combination with zidovudine, results in a significant reduction in the risk of disease progression and mortality.

Lamivudine and zidovudine have been widely used as components of antiretroviral combination therapy with other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse transcriptase inhibitors [NNRTIs]).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy. Subjects receiving lamivudine and zidovudine with or without additional concomitant antiretroviral therapies and who already present with the M184V mutant virus also experience a delay in the onset of mutations that confer resistance to zidovudine and stavudine (thymidine analogue mutations; TAMs).

The relationship between in vitro susceptibility of HIV to lamivudine and zidovudine and clinical response to lamivudine/zidovudine containing therapy remains under investigation.

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of adult patients with chronic HIV infection (for details see the prescribing information for Zeffix). However, for the treatment of HIV infection only a 300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.

Pharmacokinetics

Absorption
Lamivudine and zidovudine are well absorbed from the gastrointestinal tract. The bioavailability of oral lamivudine in adults is normally between 80-85% and for zidovudine 60-70%.

A bioequivalence study compared lamivudine + zidovudine combination with lamivudine 150 mg and zidovudine 300 mg tablets taken together. The effect of food on the rate and extent of absorption was also studied. This combination medication was shown to be equivalent to lamivudine 150 mg and zidovudine 300 mg given as separate tablets, when administered to fasting subjects.

Following a single dose of the medication in healthy volunteers, mean (CV) lamivudine and zidovudine C_max values were 1.6 µg/mL (32%) and 2.0 µg/mL (40%), respectively and the corresponding values for AUC (area under the concentration-time curve) were 6.1 µg h/mL (20%) and 2.4 µg h/mL (29%) respectively. The median (range) lamivudine and zidovudine t_max values were 0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours respectively. The extent of lamivudine and zidovudine absorption (based on AUC_∞ value) and estimates of half-life following administration of the medication with food were similar when compared to fasting subjects, although the rates of absorption were slowed. Based on these data the medicinal product may be administered with or without food.

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality of the medication, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

Distribution
Intravenous studies with lamivudine and zidovudine showed that the mean apparent volume of distribution is 1.3 and 1.6 l/kg respectively. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (< 36% serum albumin in vitro). Zidovudine plasma protein binding is 34% to 38%. Interactions with other medicinal products involving binding site displacement are not anticipated with Duovir.

Data show that lamivudine and zidovudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid. The mean ratios of CSF/serum lamivudine and zidovudine concentrations 2-4 hours after oral administration were approximately 0.12 and 0.5 respectively. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

Biotransformation
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%) and low plasma binding.

The 5′-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50–80% of the administered dose eliminated by renal excretion. 3′-amino-3′-deoxythymidine has been identified as a metabolite of zidovudine following intravenous dosing.

Elimination
Lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance ≤50 mL/min (see Section Dosage and administration).

In case of intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the mean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrations are increased in patients with advanced renal failure.

Pharmacokinetics in children
In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and at all dose levels studied in adults and children, the bioavailability was between 60-74% with a mean of 65%. Css_max levels were 4.45 μM (1.19 μg/mL) following a dose of 120 mg zidovudine (in solution)/m² body surface area and 7.7 μM (2.06 μg/mL) at 180 mg/m2 body surface area. Dosages of 180 mg/m² four times daily in children produced similar systemic exposure (24-hour AUC 40.0 h μM or 10.7 h μg/mL) as doses of 200 mg six times daily in adults (40.7 h μM or 10.9 h μg/mL).

In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were evaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again after switching to 180 mg/m² twice daily. Systemic exposures (daily AUC and C_max) in plasma from the twice daily regimen appeared equivalent to those from the same total daily dose given in three divided doses.

In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in paediatric patients below 12 years of age. Systemic clearance values were greater in younger paediatric patients and decreased with age, approaching adult values around 12 years of age. Due to these differences, the recommended dose for lamivudine in children (aged more than three months and below 12 years, weighing less than 30 kg) is 4 mg/kg twice a day. This dose will achieve an average AUC_0-12 ranging from approximately 3,800 to 5,300 ng h/mL. Recent findings indicate that exposure in children < 6 years of age may be reduced by about 30% compared with other age groups. Further data addressing this issue are currently awaited. At present, the available data do not suggest that lamivudine is less efficacious in this age group.

Pharmacokinetics in pregnancy
The pharmacokinetics of lamivudine and zidovudine were similar to that of non-pregnant women.

Antiretroviral combination therapy for the treatment of HIV infection (see Section Dosage and administration).

Therapy should be initiated by a physician experienced in the management of HIV infection.
Duovir may be administered with or without food.

To ensure dosing accuracy, the tablets should be swallowed without crushing. For patients who are unable to swallow tablets, tablets may be crushed and added to a small amount of semi-solid food or liquid. All of this mixture should be consumed immediately (see Section Pharmacokinetics).

• Adults and adolescents weighing at least 30 kg: the recommended dose of Duovir e is one tablet twice daily.
• Children weighing between 21 kg and 30 kg: the recommended dose of Duovir is one-half tablet taken in the morning and one whole tablet taken in the evening.
• Children weighing from 14 kg to 21 kg: the recommended dose of Duovir is one-half tablet taken twice daily.

The dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling and supported by data from clinical studies using the individual components lamivudine and zidovudine. A pharmacokinetic overexposure of zidovudine can occur, therefore close safety monitoring is warranted in these patients. If gastrointestinal intolerance occurs in patients weighing 21-30 kg, an alternative dosing schedule with one-half tablet taken thrice daily can be applied in attempt to improve tolerability.

Duovir tablets should not be used for children weighing less than 14 kg, since doses cannot be appropriately adjusted for the weight of the child. In these patients, lamivudine and zidovudine should be taken as separate formulations according to the prescribed dosing recommendations for these products. For these patients and for patients, who are unable to swallow tablets, oral solutions of lamivudine and zidovudine are available.

For situations where discontinuation of therapy with one of the active substances of Duovir (lamivudine/zidovudine), or dose reduction is necessary separate preparations of lamivudine and zidovudine are available in tablets/capsules and oral solution.

Special populations

Patients with renal impairment
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.

Patients with hepatic impairment
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. As dosage adjustments 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.

Dosage adjustments in patients with haematological adverse reactions
Dosage adjustment of zidovudine may be necessary if the haemoglobin level falls below 9 g/dL or 5.59 mmol/L or the neutrophil count falls below 1.0×10⁹/L (see Sections Contraindications and Special warnings and precautions for use). As dosage adjustment of lamivudine/zidovudine is not possible when taking Duovir medicinal product, separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the individual prescribing information for these medicinal products.

Elderly patients
No specific data are available on elderly patients taking Duovir. However special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.

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.

As Duovir contains lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected. Currently 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 (see Section Special warnings and precautions for use).

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Duovir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Duovir should not be continued (see Section Special warnings and precautions for use).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Section Special warnings and precautions for use).

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) 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 (see Section Special warnings and precautions for use).

Cases of osteonecrosis have been reported in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see Section Special warnings and precautions for use).

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). Undesirable effects listed below by organ systems are presented in order of decreasing seriousness.

Lamivudine

Blood and lymphatic systems disorders: uncommon – neutropenia and anaemia (both occasionally severe), thrombocytopenia; very rare – pure red cell aplasia.

Metabolism and nutrition disorders: very rare – lactic acidosis.

Nervous system disorders: common – headache, insomnia; very rare – peripheral neuropathy (or paraesthesiae).

Respiratory, thoracic and mediastinal disorders: common – cough, nasal symptoms.

Gastrointestinal disorders: common – nausea, vomiting, abdominal pain or cramps, diarrhoea; rare – pancreatitis, rises in serum amylase.

Hepatobiliary disorders: uncommon – transient rises in liver enzymes (AST, ALT); rare – hepatitis.

Skin and subcutaneous tissue disorders: common – rash, alopecia; rare – angioedema.

Musculoskeletal and connective tissue disorders: common – arthralgia, muscle disorders; rare – rhabdomyolysis.

General disorders and administration site conditions: common – fatigue, malaise, fever.

Zidovudine

The adverse reactions profile with the use of Duovir appears similar for adults and adolescents. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leukopenia. 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 in patients with CD4 cell counts less than 100/mm³ (see Section Special warnings and precautions for use).

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and vitamin B12 levels were low at the start of zidovudine therapy.

Blood and lymphatic system disorders: common – anaemia, neutropenia and leukopenia; uncommon – thrombocyopenia and pancytopenia (with marrow hypoplasia); rare – pure red cell aplasia; very rare – aplastic anaemia.

Metabolism and nutrition disorders: rare – lactic acidosis in the absence of hypoxaemia, anorexia.

Psychiatric disorders: rare – anxiety and depression.

Nervous system disorders: very common – headache; common – dizziness; rare – insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions.

Cardiac disorders: rare – cardiomyopathy.

Respiratory, thoracic and mediastinal disorders: uncommon – dysponoea; rare – cough.

Gastrointestinal disorders: very common – nausea; common – vomiting, abdominal pain and diarrhoea; uncommon – flatulence; rare – oral mucosa pigmentation, taste perversion and dyspepsia, pancreatitis.

Hepatobiliary disorders: common – raised blood levels of liver enzymes and bilirubin; rare – liver disorders such as severe hepatomegaly with steatosis.

Skin and subcutaneous tissue disorders: uncommon – rash and pruritus; rare – nail and skin pigmentation, urticaria and sweating.

Musculoskeletal and connective tissue disorders: common – myalgia; uncommon – myopathy.

Renal and urinary disorders: rare – frequent urination.

Reproductive system and breast disorders: rare – gynaecomastia.

General disorders and administration site conditions: common – malaise; uncommon – fever, generalized pain and asthenia; rare – chills, chest pain and influenza-like syndrome.

Healthcare professionals are asked to report any suspected adverse reactions after authorization of the medicinal product to “Center for Examinations and Tests in Health Service” Republican Unitary Enterprise. Website: www.rceth.by.

Hypersensitivity to lamivudine, zidovudine or to any of the auxiliary substances.

Zidovudine is contraindicated in patients with abnormally low neutrophil counts (< 0.75 x 10⁹/L), or abnormally low haemoglobin levels (< 7.5 g/dL or 4.65 mmol/L). Duovir is therefore contra-indicated in these patients (see Section Special warnings and precautions for use).

There is limited experience of overdosage with Duovir. No specific symptoms or signs have been identified following acute overdose with zidovudine or lamivudine apart from those listed as undesirable effects. None of these cases resulted in a fatal outcome, and the condition of all patients returned to normal.

If overdosage occurs the patient should be monitored for evidence of toxicity (see Section Undesirable effects), and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been clinically studied. Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine, but enhance the elimination of the glucuronide metabolite. For more details physicians should refer to the individual prescribing information for lamivudine and zidovudine.

Duovir contains lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to lamivudine/zidovudine. Clinical studies have shown that there are no clinically significant interactions between lamivudine and zidovudine.

Zidovudine is primarily metabolised by UGT enzymes; co-administration of inducers or inhibitors of UGT enzymes could alter zidovudine exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters; co-administration of lamivudine with OCT inhibitors or nephrotoxic drugs may increase lamivudine exposure.

Lamivudine and zidovudine are not significantly metabolised by cytochrome P₄₅₀ enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major cytochrome P₄₅₀ enzymes.

Interaction studies have only been performed in adults. The list below should not be considered exhaustive but is representative of the classes studied.

Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; C_max = maximum observed concentration; CL/F = apparent oral clearance.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see Section Special warnings and precautions for use).

Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive medicinal products (e.g., systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant therapy with Duovir and any of these medicinal products is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced. Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine with cotrimoxazole (see interaction information above relating to lamivudine and co-trimoxazole), aerosolized pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Appropriate precautions should be taken.

The special warnings and precautions relevant to both lamivudine and zidovudine are included in this section. There are no additional precautions and warnings relevant to Duovir combination.

It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see Section Dosage and administration). Physicians should refer to the individual prescribing information for these medicinal products.

The concomitant use of stavudine with zidovudine should be avoided (see Section Drug-to-drug interactions).

Opportunistic infections
Patients receiving Duovir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of HIV infection.

Haematological adverse reactions
Anaemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should therefore be carefully monitored (see Section Contraindications) in patients receiving Duovir. These haematological effects are not usually observed before four to six weeks therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.

In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months. Additionally, dosage adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with Duovir, or in patients with pre-existing bone marrow compromise e.g., haemoglobin < 9 g/dL (5.59 mmol/L) or neutrophil count < 1.0 x 10⁹/L (see Section Dosage and administration). As dosage adjustment of Duovir is not possible separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the individual prescribing information for these medicinal products.

Pancreatitis
Cases of pancreatitis have occurred rarely in patients treated with lamivudine and zidovudine. However, it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Duovir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Mitochondrial toxicity
In vitro and in vivo studies indicate that nucleosides and nucleotide analogues may impact mitochondrial function to a variable degree. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues (including HIV-negative children) must be under careful clinical and laboratory control; if appropriate signs and symptoms occur, it is necessary to conduct a full examination for the presence of possible mitochondrial dysfunction. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Lipoatrophy
Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may not be reversible when switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and combined zidovudine-containing medicinal products. Patients should be switched to an alternative regimen if there is suspicion of lipoatrophy development.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. The issue concerning the need to monitor blood lipids and glucose on an empty stomach should be considered. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterium infections, and pneumocystic pneumonia (P. carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease) 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.

Liver disease
If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV), additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the prescribing information for Zeffix medicinal product.

The safety and efficacy of zidovudine has not been established in patients with significant underlying liver disorders.

Patients with chronic hepatitis B or C and treated with CART are at an increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If Duovir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication for 4 months is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART). Such patients should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Patients co-infected with hepatitis C virus
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see Section Drug-to-drug interactions).

Osteonecrosis
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Duovir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

The combination of lamivudine with cladribine is not recommended (see Section Drug-to-drug interactions).

Pregnancy
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 Duovir 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 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 (see Section Special warnings and precautions for use).

Breast-feeding
Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in serum. It is recommended that mothers infected by HIV do not breast-feed their infants in order to avoid transmission of HIV.

Fertility
Neither zidovudine nor lamivudine have shown evidence of impairment of fertility in studies in male and female rats. There are no data on their effect 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.

High-density polyethylene bottles containing 60 tablets. One bottle with a patient information leaflet, packed in a carton.

Do not store above 30°C. Keep away from children.

3 years. Do not use after the expiration date.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus,
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en