COMBIVIR Film-coated tablet Ref.[10508] Active ingredients: Lamivudine Zidovudine Zidovudine and Lamivudine

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 the combination Combivir.

It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see section 4.2). In these cases the physician should refer to the individual prescribing information for these medicinal products.

The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).

Opportunistic infections

Patients receiving Combivir 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 leucopenia (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 4.3) in patients receiving Combivir. 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 Combivir, or in patients with pre-existing bone marrow compromise e.g. haemoglobin <9 g/dl (5.59 mmol/l) or neutrophil count <1.0 × 10⁹/l (see section 4.2). As dosage adjustment of Combivir 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 Combivirshould be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Lactic acidosis

Lactic acidosis usually associated with hepatomegaly and hepatic steatosis has been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain) non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with zidovudine should be discontinued if there is symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. 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 rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown etiology particularly neurologic findings. 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 zidovudine-containing products (Combivir and Trizivir). Therapy 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. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune Reactivation 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, generalised and/or focal mycobacterium infections, and Pneumocystis jirovecii pneumonia (often referred to as PCP). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. 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.

Liver disease

If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SmPC.

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 combination antiretroviral therapy 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 Combivir 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, and 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 4.5).

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.

Combivir 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 4.5).

Administration in subjects with moderate renal impairment

Patients with a creatinine clearance between 30 and 49 mL/min receiving Combivir 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 Combivir 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 Combivir 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 Combivir. Combivir should be discontinued and the individual components should be used to construct the treatment regimen.

Excipients

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Combivir contains lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to Combivir. 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 (OCTs); 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 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 4.4).

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 Combivir 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 cotrimoxazole), aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.

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 Combivir may inhibit cellular DNA replication and zidovudine has been shown to be transplacental carcinogen in one animal study (see section 5.3). 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 Combivir 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 4.4).

Breast-feeding

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.

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 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.

As Combivir contains lamivudine and zidovudine, 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 (see section 4.4).

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving Combivir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Combivir should not be continued (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

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 (see section 4.4).

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 (see section 4.4).

Lamivudine

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.

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 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 (see section 4.4).

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.

Blood and lymphatic system disorders

Common: Anaemia, neutropenia and leucopenia

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: Dyspnoea

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: Urinary frequency

Reproductive system and breast disorders

Rare: Gynaecomastia

General disorders and administration site conditions

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.