Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Epivir is not recommended for use as monotherapy.
In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see section 4.2).
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily regimen.
Patients receiving Epivir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
Cases of pancreatitis have occurred rarely. However it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
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.
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.
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.
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 SPC.
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 Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see Zeffix SPC).
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 (see section 4.8).
In a study performed in paediatric patients (see section 5.1 ARROW study), lower rates of virologic suppression and more frequent viral resistance were reported in children receiving the oral solution of Epivir as compared to those receiving the tablet formulation. Whenever possible in children, Epivir as tablet formulation should preferably be used.
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.
Epivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine (see section 4.5).
The combination of lamivudine with cladribine is not-recommended (see section 4.5).
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.
Interaction studies have only been performed in adults.
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis should be avoided.
The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine.
A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine (see section 5.2).
Due to similarities, Epivir should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Epivir should not be taken with any other medicinal products containing lamivudine (see section 4.4).
In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4).
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely.
Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of Epivir with medicinal products containing sorbitol or other osmotic acting poly- alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.
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. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans.
More than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Epivir can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on those data.
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.
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 infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Following oral administration lamivudine was 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. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Studies in animals showed that lamivudine had no effect on fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
The following adverse reactions have been reported during therapy for HIV disease with Epivir.
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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), 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 paraesthesia)
Common: Cough, nasal symptoms
Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare: Pancreatitis, elevations in serum amylase
Uncommon: Transient elevations in liver enzymes (AST, ALT)
Rare: Hepatitis
Common: Rash, alopecia
Rare: Angioedema
Common: Arthralgia, muscle disorders
Rare: Rhabdomyolysis
Common: Fatigue, malaise, fever
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 combined antiretroviral exposure (CART). The frequency of which is unknown (see section 4.4).
1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 5.1). No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.
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.
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