4.1. Therapeutic indications

Lamivudine Mylan is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

4.2. Posology and method of administration

The therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults, adolescents and children (weighing at least 25 kg)

The recommended dose of Lamivudine Mylan is 300 mg daily. This may be administered as either 150 mg twice daily or 300 mg once daily (see section 4.4).

Children (weighing less than 25 kg)

Dosing according to weight bands is recommended for lamivudine tablets.

Children weighing ≥20 kg to <25 kg

The recommended dose is 225 mg daily. This may be administered as either 75 mg (one-half of a 150 mg tablet) taken in the morning and 150 mg (one whole 150 mg tablet) taken in the evening, or 225 mg (one and a half 150 mg tablets) taken once daily.

Children weighing 14 to <20 kg

The recommended dose is 150 mg daily. This may be administered as 75 mg (one-half of a 150 mg tablet) taken twice daily, or 150 mg (one whole 150 mg tablet) taken once daily.

Children less than three months of age

The limited data available are insufficient to propose specific dosage recommendations (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take the recommended once daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the recommended once daily dose (as described above) approximately every 24 hours. When changing back to a twice daily regimen, patients should take the recommended twice daily dose approximately 24 hours after the last once daily dose.

Special populations

Elderly

No specific data are available, 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.

Renal impairment

Lamivudine concentrations are increased in patients with moderate to severe renal impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution presentation of lamivudine for patients whose creatinine clearance falls below 30 ml/min (see tables).

Dosing recommendations – Adults, adolescents and children (weighing at least 25 kg)

Creatinine clearance (ml/min)

First dose

Maintenance dose

≥50

300 mg

or

150 mg

300 mg once daily

or

150 mg twice daily

30 to <50

150 mg

150 mg once daily

<30

As doses below 150 mg are needed, the use of the oral solution is recommended

15 to <30

150 mg

100 mg once daily

5 to <15

150 mg

50 mg once daily

<5

50 mg

25 mg once daily

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in adults, it is recommended that the dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults. Lamivudine oral solution may be the most appropriate formulation to achieve the recommended dose in children with renal impairment aged at least 3 months and weighing less than 25 kg.

Dosing recommendations – Children aged at least 3 months and weighing less than 25 kg

Creatinine clearance (ml/min)

First dose

Maintenance dose

≥50

10mg/kg

or

5mg/kg

10mg/kg once daily

or

5mg/kg twice daily

30 to <50

5mg/kg

5mg/kg once daily

15 to <30

5mg/kg

3.3mg/kg once daily

5 to <15

5mg/kg

1.6mg/kg once daily

<5

1.6mg/kg

0.9mg/kg once daily

Hepatic impairment

Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

Method of administration

For oral use.

Lamivudine Mylan may be administered with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.

Lamivudine is available as an oral solution for children over three months of age and who weigh less than 14 kg or for patients who are unable to swallow tablets.

Patients changing between lamivudine oral solution and lamivudine tablets should follow the dosing recommendations that are specific for the formulation (see section 5.2).

Alternatively, for patients who are unable to swallow the tablets, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Lamivudine is not recommended for use as monotherapy.

Renal impairment

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).

Triple nucleoside therapy

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.

Opportunistic infections

Patients receiving lamivudine 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.

Pancreatitis

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 Lamivudine Mylan should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to, 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 (hyperlactataemia, hyperlipasemia). These reactions 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 present with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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 corresponding 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 Lamivudine Mylan 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 corresponding 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).

Paediatric population

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 lamivudine as compared to those receiving the tablet formulation. Whenever possible in children, lamivudine as tablet formulation should preferably be used.

Osteonecrosis

Although the aetiology 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.

Drug interactions

Lamivudine Mylan 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).

Lamivudine Mylan contains sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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, lamivudine should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Lamivudine Mylan 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.

Co-administration 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 co-administration of lamivudine 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 co-administration cannot be avoided.

4.6. Fertility, pregnancy and lactation

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.

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 1,000 outcomes from the first trimester and more than 1,000 outcomes from the second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Lamivudine 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.

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 infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Breast-feeding

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 breast-fed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breast-fed 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 women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

FertilityStudies in animals showed that lamivudine had no effect on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

The following adverse reactions have been reported during therapy for HIV disease with 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system 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 paraesthesia)

Respiratory, thoracic and mediastinal disorders

Common: Cough, nasal symptoms

Gastrointestinal disorders

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea

Rare: Pancreatitis, elevations in serum amylase

Hepatobiliary disorders

Uncommon: Transient elevations 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

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).

Paediatric population

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 of suspected adverse reactions

Reporting of 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose.

Treatment

If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.