Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

WHO-PQ RECOMMENDED
SUMMARY OF PRODUCT CHARACTERISTICS

This summary of product characteristics focuses on uses of the medicine covered by WHO’s
Prequalification Team - Medicines. The recommendations for use are based on WHO guidelines
and on information from stringent regulatory authorities. *The medicine may be authorised for additional or different uses by national medicines regulatory
authorities.

Page 1 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

1.

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

NAME OF THE MEDICINAL PRODUCT[HA514 trade name] †2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains:
Lamivudine 300 mg and Tenofovir Disoproxil Fumarate 300 mg (equivalent to tenofovir disoproxil 245 mg
or tenofovir 136 mg)
Each tablet also contains 8 mg of lactose monohydrate
For a full list of excipients see 6.1

3.

PHARMACEUTICAL FORM

Film-coated tablet
White to off-white coloured, capsule shaped, biconvex, film-coated tablets debossed 'CL71' on one side of
the tablet and having plain surface on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications[HA514 trade name] is indicated in combination with other antiretroviral medicinal products for thetreatment of human immunodeficiency virus (HIV-1) infection in patients weighing at least 30 kg or more.
The choice of [HA514 trade name] to treat antiretroviral-experienced patients with HIV-1 infection should
be based on individual viral resistance testing or the treatment history of the patient.
[HA514 trade name] may be used for pre-exposure prophylaxis (PrEP) as an additional prevention choice for
adults and adolescents (weighing at least 35 kg) at substantial risk of HIV infection as part of combination
prevention approaches.
Consideration should be given to official guidelines for prevention and treatment of HIV-1 infection (e.g.
issued by WHO).
For use of antiretroviral agents for post-exposure prophylaxis consult the most recent official guidelines, e.g.
those by WHO.
4.2

Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV infection.
Posology
Adult and adolescentsThe recommended dose of [HA514 trade name] is one tablet, taken once daily.
For PrEP, alternative dose recommendations may apply to specific subgroups of HIV-1 uninfectedindividuals at risk for HIV-infection. For use of [HA514 trade name] for PrEP, consult the most recent
official guidelines, e.g. those by WHO.

†

Trade names are not prequalified by WHO. This is the national medicines regulatory agency’s responsibility.
Page 2 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Special populations
Children and adolescents
HIV-therapy: [HA514 trade name] should not be used in patients weighing less than 30 kg since appropriate
dose adjustments cannot be achieved with this product (see section 5.2). For patients weighing less than
30 kg other formulations with lower amounts of the active substances are available.
PrEP: [HA514 trade name] should not be used in adolescents weighing less than 35 kg due to insufficient
data on safety and efficacy (see section 5.2).
Elderly[HA514 trade name] should be administered with caution to elderly patients (see section 4.4).
Renal impairment[HA514 trade name] is not recommended for use in patients with creatinine clearance < 50 ml/minute (seesections 4.4. and 5.2), as appropriate dose adjustments are not possible. For these patients, separate
formulations of lamivudine and tenofovir disoproxil should be used.
[HA514 trade name] should not be used for PrEP in HIV-1 uninfected individuals with estimated creatinine
clearance below 60 ml/minute.
Hepatic impairment
No dose adjustment is required (see sections 4.4 and 5.2).
Discontinuation of therapy
Where discontinuation of therapy of HIV-1 infection with one of the components of [HA514 trade name] isindicated or where dose modification is necessary, separate preparations of lamivudine and tenofovir
disoproxil should be used. If [HA514 trade name] is discontinued in patients co-infected with HIV andhepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis(see section 4.4).
Advice on missed dose
If a dose of [HA514 trade name] is missed within 12 hours of the time it is usually taken, the individual
should take the medicine as soon as possible and resume the normal dosing schedule with the next due dose.
If the patient misses a dose of [HA514 trade name] by more than 12 hours and it is almost time for the next
dose, the individual should not take the missed dose and simply resume the usual dosing schedule.
If the individual vomits within 1 hour of taking [HA514 trade name], another tablet should be taken. There isno need to take an extra dose if vomiting occurs more than 1 hour after taking [HA514 trade name].
Method of administration:
It is recommended that [HA514 trade name] be swallowed whole with water. [HA514 trade name] can betaken with food or between meals.
For young children or patients not able to swallow the tablets whole, the tablets may be crushed and added toa small amount of semi-solid food or liquid, all of which should be consumed immediately.
4.3

Contraindications

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

Page 3 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

4.4

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Special warnings and precautions for use

HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir therapy (seebelow Co-infection with HIV-1 and hepatitis B). In turn, HBV antibody testing should be offered to allindividuals before initiating tenofovir therapy.
Pre-exposure prophylaxis
Comprehensive Management to Reduce the Risk of Acquiring HIV-1:[HA514 trade name] should be used for pre-exposure prophylaxis only as part of a comprehensive
prevention strategy that includes other prevention measures, such as safer sex practices, because preexposure prophylaxis is not always effective in preventing the acquisition of HIV-1 (see section 5.1).
Uninfected individuals should be counselled about safer sex practices that include consistent and correct useof condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for othersexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhoea).
Uninfected individuals should be counselled to strictly adhere to the recommended [HA514 trade name]dosing schedule. The effectiveness of tenofovir disoproxil in reducing the risk of acquiring HIV-1 correlates
strongly with adherence as demonstrated by drug levels in clinical trials.
The risk for HIV-1 acquisition should be assessed at each visit.
Only an individual who has been confirmed HIV-negative should use [HA514 trade name] to prevent
acquiring HIV-1 infection. Use of tenofovir disoproxil alone in an individual with undetected HIV-1
infection can lead to the virus developing resistance to the drug. Individuals with HIV-1 infection must betreated with a combination of antiretrovirals.
Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during theacute stage of infection. Prior to initiating [HA514 trade name] for a PrEP indication, seronegative
individuals should be evaluated for current or recent signs or symptoms consistent with acute viral infections(e.g., fever, fatigue, myalgia, skin rash, etc.) and asked about potential exposure events (e.g., unprotected, orcondom broke during sex with an HIV-1 infected partner) that may have occurred within the last month.
If the patient has symptoms consistent with acute viral infection, and exposure to such an infection within theprevious month is suspected, the start of PrEP should be delayed for at least one month. HIV-1 status shouldbe then reconfirmed using a reliable test.
While using [HA514 trade name]for PrEP, HIV-1 screening tests should be repeated at least every 3 months.
If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP
should be discontinued until negative infection status is confirmed using a reliable test for diagnosing HIV-1.
Preliminary data for a combination of tenofovir disoproxil and emtricitabine ‡ indicate that the time before
PrEP with tenofovir disoproxil is fully effective may be up to seven days for anal sex and up to three weeks
for vaginal sex. Individuals who wish to discontinue PrEP should be advised to continue taking tenofovir
disoproxil for at least 4 weeks after the last potential HIV exposure.
Transmission of HIV
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the riskof sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should betaken in accordance with national guidelines.
‡

Based on a systematic review it is suggested that emtricitabine and lamivudine are pharmacologically equivalent, andhence clinically interchangeable for therapy of HIV infection. Limited data are also indicative of a similar
pharmacological effect in PrEP. Therefore, herein reference is made also to data obtained with emtricitabine.
Page 4 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Mitochondrial dysfunction following exposure in utero
Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is mostpronounced 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 havepredominantly 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 beenreported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders aretransient or permanent is currently unknown. These findings should be considered for any child exposed inutero 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.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Suchchanges may in part be linked to disease control and life style. For lipids, there is in some cases evidence fora 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, typically in the first few weeks or months after
initiation of combination ART, an inflammatory reaction to asymptomatic or residual opportunistic
pathogens (e.g. CMV retinitis, mycobacterial infections, Pneumocystis carinii pneumonia) may arise andcause serious clinical conditions or aggravation of symptoms. Treatment should be instituted whennecessary.
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.
Opportunistic infections
HIV-1 infected patients receiving [HA514 trade name] or any other antiretroviral therapy may still develop
opportunistic infections and other complications of HIV infection. Therefore patients should remain underclose clinical observation by heath care providers experienced in the treatment of these associated HIV
diseases.
Renal function
Lamivudine and tenofovir disoproxil are primarily excreted by the kidneys, through a combination ofglomerular filtration and active tubular secretion. [HA514 trade name] is not recommended for patients withmoderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe
renal impairment require a dose adjustment of lamivudine and tenofovir disoproxil that cannot be achieved
with the combination tablet (see sections 4.2 and 5.2).
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil in clinical practice(see section 4.8).
It is recommended that creatinine clearance /estimated glomerular function is calculated in all patients prior
to initiating therapy and as clinically appropriate during therapy with [HA514 trade name]. If the creatinine
test is routinely available, the estimated glomerular filtration rate at baseline should be used before initiating
tenofovir disoproxil containing regimens.
Page 5 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

If the creatinine test is not routinely available urine dipsticks may be used to detect glycosuria or severe
tenofovir disoproxil nephrotoxicity in individuals without risk factors.
Creatinine testing is particularly advisable for high-risk patients (those who are older or have underlying
renal disease, long-term diabetes or uncontrolled hypertension concomitant with boosted PIs or nephrotoxic
drugs) to detect and limit further progression of renal impairment. Benefit and risks should be carefully
weighed.
If available, also serum phosphate should be measured in these patients. If serum phosphate is < 1.5 mg/dl(0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving this medicine renal
function must be re-evaluated within one week, including measurements of blood glucose, blood potassium
and urine glucose concentrations (see section 4.8, proximal tubulopathy).
Since [HA514 trade name] is a combination product and the dosing interval of the individual components
cannot be altered, treatment with this medicine must be interrupted in patients with confirmed creatinine
clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).
Interrupting treatment should also be considered in case of progressive decline of renal function when noother cause has been identified. Where discontinuation of therapy with one of the components is indicated orwhere dose modification is necessary, separate preparations of lamivudine and tenofovir disoproxil areavailable.
This medicine should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g.
high-dose or multiple non-steroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, foscarnet,
ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2). If concomitant use of [HA514 trade name]and nephrotoxic agents is unavoidable, renal function must be monitored weekly (see section 4.5).
Tenofovir disoproxil has not been clinically evaluated in patients receiving medicinal products which are
secreted by the same renal pathway, including the transport proteins human organic anion transporter(hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport
proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir.
Consequently, the pharmacokinetics of these medicinal products, which are secreted by the same renal
pathway including transport proteins hOAT 1 and 3 or MRP 4, might be modified if they are coadministered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by
the same renal pathway is not recommended, but if such use is unavoidable, renal function should bemonitored weekly (see section 4.5).
Pre-exposure Prophylaxis[HA514 trade name] should not be used for PrEP in individuals with an estimated creatinine clearance below
60 ml/minute. Creatinine clearance should be measured every 3 months during the first 12 months andannually thereafter. If the estimated creatinine clearance decreases in individuals using this medicine for
PrEP, potential causes should be evaluated and potential risks and benefits of continued use re-assessed.
Elderly
Elderly patients are more likely to have decreased renal function; therefore caution should be exercised whentreating elderly patients with [HA514 trade name]
Bone effects
In a controlled clinical study in adults comparing tenofovir disoproxil and stavudine (each in combination
with lamivudine and efavirenz), bone mineral density of the spine decreased and bone biomarkers changed
from baseline in both treatment groups, but the changes were significantly greater in the tenofovir disoproxil
group at 144 weeks. Decreases in bone mineral density of the hip were significantly greater in this groupuntil 96 weeks. However, over 144 weeks, the risk of fractures was not increased and there was no evidenceof clinically relevant bone abnormalities.
In HIV-1 infected adolescents 12 years of age and older, the mean rate of bone gain was less in the tenofovir
disoproxil -treated group compared to the placebo group. Skeletal growth (height) appeared to be unaffected.
Page 6 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Markers of bone turnover in tenofovir disoproxil-treated adolescents suggest increased bone turnover,consistent with the effects observed in adults. Due to the possible effects of tenofovir on bone metabolism,[HA514 trade name] should only be used in adolescents under the age of 18 if the benefits are considered to
exceed the risk (see also section 4.8).
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal
tubulopathy (see section 4.8). If bone abnormalities are suspected, then appropriate consultation should beobtained.
Osteonecrosis
Cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or longterm exposure to combination antiretroviral therapy. Their etiology is considered to be multifactorial(including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index).
Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness ordifficulty in movement.
Pancreatitis
Cases of pancreatitis have occurred rarely. However it is not clear whether these cases were due to theantiretroviral treatment or to the underlying HIV disease. Treatment with [HA514 trade name] should be
stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
Liver disease
The safety and efficacy of [HA514 trade name] have not been established in patients with significant
underlying liver disorders. Patients with pre-existing liver dysfunction, including chronic active hepatitis,
have an increased frequency of liver function abnormalities during combination antiretroviral therapy, andshould be monitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered.
Safety and efficacy data of tenofovir disoproxil are very limited in liver transplant patients.
There are limited data on the safety and efficacy of tenofovir disoproxil in HBV infected patients withdecompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These patients may be at
higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal
parameters should be closely monitored in this patient population during treatment with lamivudine/tenofovir
disoproxil.
Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infections
Health care providers should refer to current relevant treatment guidelines for the optimal management of
HIV infection in patients co-infected with HBV or HCV.
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 reactions. In case of concomitant antiviral therapy forhepatitis B or C, please refer also to the relevant product information for these medicinal products.
Lamivudine and tenofovir disoproxil are also active against HBV. Therefore, discontinuation of [HA514
trade name] in patients co-infected with HIV and HBV may be associated with severe acute exacerbations ofhepatitis. Patients co-infected with HIV and HBV who discontinue [HA514 trade name] should be closely
monitored with both clinical and laboratory follow-up for at least six months after stopping treatment. If
appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or
cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis maylead to hepatic decompensation.

Page 7 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Exacerbations of hepatitis
Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and arecharacterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may
increase in some patients (see section 4.8). In patients with compensated liver disease, these increases inserum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic
decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following
hepatitis exacerbation, and therefore should be monitored closely during therapy.
Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who
have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBVDNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, havebeen reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory
follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption ofhepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment
discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic
decompensation.
Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.
Antivirals against HCV
Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir,
especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic
enhancer (e.g. ritonavir).
The safety of tenofovir disoproxil in the setting of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer has not been established. The potential
risks and benefits associated with co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV
protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased
risk of renal dysfunction.
Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir
concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored foradverse reactions related to tenofovir disoproxil.
Co-administration of other medicinal products
As a fixed combination, [HA514 trade name] should not be administered concomitantly with other medicinal
products containing any of the same active components, lamivudine or tenofovir disoproxil.
Due to similarities with lamivudine, [HA514 trade name] should not be administered concomitantly withother cytidine analogues, such as emtricitabine. [HA514 trade name] should not be administeredconcomitantly with medicinal products containing adefovir dipivoxil or tenofovir alafenamide.
Co-administration of tenofovir disoproxil and didanosine is not recommended since exposure to didanosine
is significantly increased following co-administration with tenofovir disoproxil (see section 4.5). Rare casesof pancreatitis and lactic acidosis, sometimes fatal, have been reported. Furthermore, co-administration of
tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decreasein CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active)
didanosine. A low dose of 250 mg didanosine co-administered with tenofovir disoproxil has been associatedwith reports of high rates of virological failure with several combinations for the treatment of HIV-1
infection.
The combination of lamivudine with cladribine is not recommended (see section 4.5).

Page 8 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Triple therapy with nucleosides/nucleotides:
There have been reports of a high rate of virological failure and of early emergence of resistance in HIV
patients when tenofovir disoproxil and lamivudine was combined with abacavir or didanosine as a once daily
regimen.
Excipients[HA514 trade name] contains a small amount of lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption may experience symptoms of
intolerance.
It is important to consider the contribution of excipients from all the medicines that the patient is taking.
4.5

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
No drug interaction studies have been conducted using lamivudine/tenofovir disoproxil tablets. Druginteraction studies have been conducted with lamivudine or tenofovir disoproxil, the components of this
fixed dose combination.
Based on the results of in vitro experiments and the known elimination pathways of lamivudine andtenofovir, the potential for CYP450-mediated interactions with other medicinal products is low.
Interactions relevant to lamivudine
Sulfamethoxazole/trimethoprim increases plasma concentrations of lamivudine but a clinically significant
effect is not expected; the patient should be monitored for lamivudine toxicity in case of marked renal
impairment or if high doses of sulfamethoxazole/trimethoprim are used (e.g. for Pneumocystis jirovecii
pneumonitis treatment).
Medicinal products, whose main route of elimination is active renal secretion via the organic cationictransport system, e.g. trimethoprim, may interact with lamivudine. Medicinal products (e.g. ranitidine,
cimetidine), which are eliminated only in part by this mechanism, were shown not to interact withlamivudine.
Due to similarities, [HA514 trade name] should not be administered concomitantly with other cytidine
analogues, such as emtricitabine. Moreover, [HA514 trade name] should not be taken with any othermedicinal products containing lamivudine (see section 4.4).
In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk ofcladribine 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 withcladribine is not recommended (see section 4.4).
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∞) and28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, chronic coadministration oflamivudine with medicinal products containing sorbitol or other osmotic acting polyalcohols ormonosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol) should be avoided. More frequentmonitoring of HIV-1 viral load, when chronic coadministration cannot be avoided, should be considered.
Interactions relevant to tenofovir
Concomitant use not recommended[HA514 trade name] should not be administered with any other medicines containing:- tenofovir disoproxil
Page 9 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

- tenofovir alafenamide- adefovir dipivoxil- didanosine (see section 4.4 and Table 2)
Renally eliminated medicinal products:
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil withmedicines that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1,
hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir, or the co-administered
medicines, or both.
Nephrotoxic medicinal products:
Use of tenofovir disoproxil should be avoided with concurrent use of a nephrotoxic medicinal product.
Examples include, but are not limited to high-dose or multiple non-steroidal anti-inflammatory drugs,
aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir andinterleukin-2 (see section 4.4).
Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administeredwith tenofovir disoproxil.
Other interactions:Interactions between [HA514 trade name] and HIV protease inhibitors, as well as antiviral agents other thanprotease inhibitors, are listed in the table below (increased exposure is indicated as “↑”, decreased exposureas “↓”, no change as “↔”,).
Interactions between tenofovir disoproxil and other medicinal products
Medicinal products by
therapeutic areas (dose in mg)
ANTI-INFECTIVES
antiretrovirals
Protease inhibitors
Atazanavir(400 mg once daily)

Atazanavir/Ritonavir(300 mg/100 mg once daily)

Lopinavir/Ritonavir(400 mg/100 mg twice daily.)

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin

Recommendation on coadministration with tenofovir
disoproxil 245 mg

Atazanavir:
AUC: ↓ 25%
Cmax: ↓ 21%
Cmin: ↓ 40%

If atazanavir and tenofovir are coadministered, atazanavir should begiven at a dose 300 mg once daily
together with ritonavir 100 mg
once daily (“ritonavir-boosting”,
see below).

Tenofovir:
AUC: ↑ 24%
Cmax: ↑ 14%
Cmin: ↑ 22%
Atazanavir:
AUC: ↓ 25%
Cmax: ↓ 28%
Cmin: ↓ 26%
Tenofovir:
AUC: ↑ 37%
Cmax: ↑ 34%
Cmin: ↑ 29%
Lopinavir/ritonavir:
No significant effect on
lopinavir/ritonavir
Page 10 of 30

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate tenofovir-associatedadverse events, including renal
disorders. Renal function should
be closely monitored (see section
4.4).
No dose adjustment isrecommended. The increased
exposure of tenofovir couldLamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

Darunavir/Ritonavir(300 mg/100 mg twice daily.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cminpharmacokinetic parameters.
Tenofovir:
AUC: ↑ 32%
Cmax: ↔
Cmin: ↑ 51%
Darunavir:
No significant effect on
darunavir/ritonavir
pharmacokinetic parameters.
Tenofovir:
AUC: ↑ 22%
Cmin: ↑ 37%

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg
potentiate tenofovir-associatedadverse events, including renal
disorders. Renal function should
be closely monitored (see section
4.4).
No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate tenofovir-associatedadverse events, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

NRTIs
Didanosine

Didanosine AUC ↑ 40-60%

Adefovir dipivoxil

AUC: ↔
Cmax: ↔

Entecavir

AUC: ↔
Cmax: ↔

No clinically significant
pharmacokinetic interactions when
tenofovir disoproxil was coadministered with entecavir.

Ledipasvir:
AUC: ↑ 96%
Cmax: ↑ 68%
Cmin: ↑ 118%

Increased plasma concentrationsof tenofovir resulting from coadministration of tenofovir
disoproxil, ledipasvir/sofosbuvir
and atazanavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwith ledipasvir/sofosbuvir and apharmacokinetic enhancer (e.g.

Hepatitis C virus antiviral agents
Ledipasvir/Sofosbuvir(90 mg/400 mg q.d.) +Atazanavir/Ritonavir(300 mg q.d./100 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)1

Sofosbuvir:
AUC: ↔
Cmax: ↔
GS-3310072:
AUC: ↔
Page 11 of 30

The risk of didanosine-related
adverse effects (e.g. pancreatitis,
lactic acidosis) appear to be
increased, and CD4 cells may
decrease significantly on coadministration. Also didanosine at
250 mg co-administered withtenofovir with several different
antiretroviral combination
regimens has been associated witha high rate of virological failure.
Co-administration of tenofovir
disoproxil and didanosine is notrecommended(see section 4.4).
Tenofovir disoproxil should not be
administered concurrently withadefovir dipivoxil (see section
4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
Cmax: ↔
Cmin: ↑ 42%
Atazanavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 63%

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg
ritonavir) has not been established.
The combination should be usedwith caution with frequent renalmonitoring, if other alternatives
are not available (see section 4.4).

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 45%
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Ledipasvir/Sofosbuvir(90 mg/400 mg q.d.) +Darunavir/Ritonavir(800 mg q.d./100 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)1

Tenofovir:
AUC: ↔
Cmax: ↑ 47%
Cmin: ↑ 47%
Ledipasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Sofosbuvir:
AUC: ↓ 27%
Cmax: ↓ 37%
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Darunavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 48%
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
Page 12 of 30

Increased plasma concentrationsof tenofovir resulting from coadministration of tenofovir
disoproxil, ledipasvir/sofosbuvir
and darunavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwith ledipasvir/sofosbuvir and apharmacokinetic enhancer (e.g.
ritonavir) has not been established.
The combination should be usedwith caution with frequent renalmonitoring, if other alternatives
are not available (see section 4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

Ledipasvir/Sofosbuvir(90 mg/400 mg q.d.) +Efavirenz/Emtricitabine/Tenofovir
disoproxil(600 mg/200 mg/245 mg q.d.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
AUC: ↑ 50%
Cmax: ↑ 64%
Cmin: ↑ 59%
Ledipasvir:
AUC: ↓ 34%
Cmax: ↓ 34%
Cmin: ↓ 34%
Sofosbuvir:
AUC: ↔
Cmax: ↔

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate adverse reactions
associated with tenofovir
disoproxil, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 98%
Cmax: ↑ 79%
Cmin: ↑ 163%
Ledipasvir/Sofosbuvir
Ledipasvir:(90 mg/400 mg q.d.) +AUC: ↔
Emtricitabine/Rilpivirine/Tenofovir Cmax: ↔
disoproxil
Cmin: ↔
(200 mg/25 mg/245 mg q.d.)
Sofosbuvir:
AUC: ↔
Cmax: ↔
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Rilpivirine:
AUC: ↔
Page 13 of 30

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate adverse reactions
associated with tenofovir
disoproxil, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

Ledipasvir/Sofosbuvir(90 mg/400 mg q.d.) +Dolutegravir (50 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 40%
Cmax: ↔
Cmin: ↑ 91%
Sofosbuvir:
AUC: ↔
Cmax: ↔
GS-3310072
AUC: ↔
Cmax: ↔
Cmin: ↔

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate adverse reactions
associated with tenofovir
disoproxil, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

Ledipasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Dolutegravir
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir/Velpatasvir(400 mg/100 mg q.d.) +Atazanavir/Ritonavir(300 mg q.d./100 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)

Tenofovir:
AUC: ↑ 65%
Cmax: ↑ 61%
Cmin: ↑ 115%
Sofosbuvir:
AUC: ↔
Cmax: ↔
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↑ 42%
Velpatasvir:
AUC: ↑ 142%
Cmax: ↑ 55%
Cmin: ↑ 301%
Atazanavir:
AUC: ↔
Cmax: ↔
Page 14 of 30

Increased plasma concentrationsof tenofovir resulting from coadministration of tenofovir
disoproxil, sofosbuvir/velpatasvir
and atazanavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwith sofosbuvir/velpatasvir and apharmacokinetic enhancer (e.g.
ritonavir) has not been established.
The combination should be usedwith caution with frequent renalmonitoring (see section 4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
Cmin: ↑ 39%

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↑ 29%
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir/Velpatasvir(400 mg/100 mg q.d.) +Darunavir/Ritonavir(800 mg q.d./100 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)

Tenofovir:
AUC: ↔
Cmax: ↑ 55%
Cmin: ↑ 39%
Sofosbuvir:
AUC: ↓28%
Cmax: ↓ 38%
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Velpatasvir:
AUC: ↔
Cmax: ↓ 24%
Cmin: ↔
Darunavir:
AUC: ↔
Cmax: ↔
Cmin: ↔

Increased plasma concentrationsof tenofovir resulting from coadministration of tenofovir
disoproxil, sofosbuvir/velpatasvir
and darunavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwith sofosbuvir/velpatasvir and apharmacokinetic enhancer (e.g.
ritonavir) has not been established.
The combination should be usedwith caution with frequent renalmonitoring (see section 4.4).

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir/Velpatasvir(400 mg/100 mg q.d.) +Lopinavir/Ritonavir

Tenofovir:
AUC: ↑ 39%
Cmax: ↑ 55%
Cmin: ↑ 52%
Sofosbuvir:
AUC: ↓ 29%
Cmax: ↓ 41%
Page 15 of 30

Increased plasma concentrationsof tenofovir resulting from coadministration of tenofovir

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)(800 mg/200 mg q.d.) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Velpatasvir:
AUC: ↔
Cmax: ↓ 30%
Cmin: ↑ 63%
Lopinavir:
AUC: ↔
Cmax: ↔
Cmin: ↔

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg
disoproxil, sofosbuvir/velpatasvir
and lopinavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwith sofosbuvir/velpatasvir and apharmacokinetic enhancer (e.g.
ritonavir) has not been established.
The combination should be usedwith caution with frequent renalmonitoring (see section 4.4).

Ritonavir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir/Velpatasvir(400 mg/100 mg q.d.) +Raltegravir(400 mg b.i.d) +Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.)

Tenofovir:
AUC: ↔
Cmax: ↑ 42%
Cmin: ↔
Sofosbuvir:
AUC: ↔
Cmax: ↔
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Raltegravir:
AUC: ↔
Cmax: ↔
Cmin: ↓ 21%
Emtricitabine:
AUC: ↔
Cmax: ↔
Page 16 of 30

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate adverse reactions
associated with tenofovir
disoproxil, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

Sofosbuvir/Velpatasvir(400 mg/100 mg q.d.) +Efavirenz/Emtricitabine/Tenofovir
disoproxil(600 mg/200 mg/245 mg q.d.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin
Cmin: ↔
Tenofovir:
AUC: ↑ 40%
Cmax: ↑ 46%
Cmin: ↑ 70%
Sofosbuvir:
AUC: ↔
Cmax: ↑ 38%
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

Concomitant administration of
sofosbuvir/velpatasvir andefavirenz is expected to decrease
plasma concentrations ofvelpatasvir. Co-administration of
sofosbuvir/velpatasvir withefavirenz-containing regimens is
not recommended.

Velpatasvir:
AUC: ↓ 53%
Cmax: ↓ 47%
Cmin: ↓ 57%
Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↑ 81%
Cmax: ↑ 77%
Cmin: ↑ 121%
Sofosbuvir/Velpatasvir
Sofosbuvir:(400 mg/100 mg q.d.) +AUC: ↔
Emtricitabine/Rilpivirine/Tenofovir Cmax: ↔
disoproxil(200 mg/25 mg/245 mg q.d.)
GS-3310072:
AUC: ↔
Cmax: ↔
Cmin: ↔
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Page 17 of 30

No dose adjustment isrecommended. The increased
exposure of tenofovir could
potentiate adverse reactions
associated with tenofovir
disoproxil, including renal
disorders. Renal function should
be closely monitored (see section
4.4).

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

Rilpivirine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir/Velpatasvir/
Voxilaprevir (400 mg/100 mg/
100 mg+100 mg q.d.)3 + Darunavir(800 mg q.d.) + Ritonavir (100 mg
q.d.) + Emtricitabine/Tenofovir
disoproxil (200 mg/245 mg q.d.)

Tenofovir:
AUC: ↑ 40%
Cmax: ↑ 44%
Cmin: ↑ 84%
Sofosbuvir:
AUC: ↔
Cmax: ↓ 30%
Cmin: N/A
GS-3310072:
AUC: ↔
Cmax:↔
Cmin: N/A
Velpatasvir:
AUC: ↔
Cmax: ↔
Cmin: ↔
Voxilaprevir:
AUC: ↑ 143%
Cmax:↑ 72%
Cmin: ↑ 300%

Increased plasma concentrationsof tenofovir resulting from
coadministration of tenofovir
disoproxil,
sofosbuvir/velpatasvir/voxilaprevir
and darunavir/ritonavir may
increase adverse reactions related
to tenofovir disoproxil, including
renal disorders. The safety oftenofovir disoproxil when usedwithsofosbuvir/velpatasvir/voxilaprevir
and a pharmacokinetic enhancer(e.g. ritonavir) has not been
established. The combination
should be used with caution withfrequent renal monitoring (seesection 4.4).

Darunavir:
AUC: ↔
Cmax: ↔
Cmin: ↓ 34%
Ritonavir:
AUC: ↑ 45%
Cmax: ↑ 60%
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔

Sofosbuvir(400 mg q.d.) +Efavirenz/Emtricitabine/Tenofovir

Tenofovir:
AUC: ↑ 39%
Cmax: ↑ 48%
Cmin: ↑ 47%
Sofosbuvir:
AUC: ↔
Cmax: ↓ 19%
Page 18 of 30

No dose adjustment is required.

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Medicinal products by
therapeutic areas (dose in mg)
disoproxil(600 mg/200 mg/245 mg q.d.)

WHOPAR Part 4

Effects on drug levels
Mean % change in AUC,
Cmax, Cmin

August 2020
Section 6 updated: May 2024

Recommendation on coadministration with tenofovir
disoproxil 245 mg

GS-3310072:
AUC: ↔
Cmax: ↓ 23%
Efavirenz:
AUC: ↔
Cmax: ↔
Cmin: ↔
Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↔
Cmax: ↑ 25%
Cmin: ↔

1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provided
similar results.
2 The predominant circulating metabolite of sofosbuvir.
3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

Studies with other medicines
There were no clinically significant pharmacokinetic interactions when [HA514 trade name] was coadministered with indinavir, efavirenz, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin,
tacrolimus, or the hormonal contraceptive norgestimate/ethinylestradiol.
Food effect
Food has no influence on the absorption of lamivudine and enhances the bioavailability of tenofovir (seesection 5.2).
4.6

Fertility, pregnancy and breastfeeding

Pregnancy
Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil or lamivudine withrespect to reproductive toxicity (see section 5.3). The safety of tenofovir in human pregnancy has not been
fully established. However, sufficient numbers of first trimester exposures have been monitored to detect atleast a twofold increase in the risk of overall birth defects. No increase in birth defects was seen for tenofovir
disoproxil or lamivudine ( www.apregistry.com/ )Breast-feeding
Lamivudine and tenofovir disoproxil are excreted into the breast milk of lactating mothers. There isinsufficient information on the effects of tenofovir in breast-feeding infants.
Current recommendations on HIV/PrEP and breast-feeding (e.g. those from the WHO) should be consulted
before advising women on this matter. Preferred options may vary depending on the local circumstances.

Page 19 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Fertility
Animal studies do not indicate harmful effects of tenofovir disoproxil and lamivudine on fertility. (seesection 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. However, users
should be informed that dizziness has been reported during treatment with tenofovir disoproxil.
Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous
tasks such as driving and operating machinery.
4.8

Undesirable effects

In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon
events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities(infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended forpatients receiving tenofovir disoproxil (see section 4.4).
Approximately one third of patients can be expected to experience adverse reactions following treatment
with tenofovir disoproxil in combination with other antiretroviral agents. These reactions are usually mild tomoderate gastrointestinal events. Approximately 1% of tenofovir disoproxil-treated adult patients
discontinued treatment due to the gastrointestinal events.
The adverse reactions considered related to tenofovir disoproxil and lamivudine are listed below by bodysystem, organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10) or common (≥1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).
Blood and lymphatic system disorders
Uncommon: neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare: pure red cell aplasia
Metabolism and nutrition disorders:
Very common: hypophosphataemia1
Uncommon: hypokalaemia1
Rare: lactic acidosis
Nervous system disorders:
Very common: dizzinessCommon: headache, insomnia
Very rare: peripheral neuropathy (or paraesthesia)
Respiratory, thoracic and mediastinal disorders
Common: cough, nasal symptoms
Very rare: dyspnoea
Gastrointestinal disorders:
Very common: diarrhoea, vomiting, nausea
Common: abdominal pain, abdominal distension, flatulence, diarrhoea
Rare: pancreatitis, elevated serum amylases
Hepatobiliary disorders:Common: increased transaminases
Rare: hepatic steatosis, hepatitis

Page 20 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

Skin and subcutaneous tissue disorders:
Very common: rash, alopecia
Rare: angioedema
Musculoskeletal and connective tissue disorders:Common: arthralgia, muscle disorders
Uncommon: rhabdomyolysis1, muscular weakness1
Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 2, myopathy1
Renal and urinary disorders:
Uncommon: increased creatinine
Rare: acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi
syndrome), nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus
General disorders and administration site conditions:
Very common: asthenia
Common: fatigue, malaise, feverThis adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally
associated with tenofovir disoproxil in the absence of this condition.
2 This adverse reaction was identified through post-marketing surveillancePre-exposure prophylaxis
In two randomised controlled HIV-prevention trials in men who have sex with men, transgender women(iPrEx trial) and serodiscordant couples (PartnersPrEP), in which 2830 uninfected adults received fixed dosecombination tablets of emtricitabine§ and tenofovir disoproxil fumarate no new adverse reactions werereported. Of those reactions, occurring in at least 2% of subjects, the following were reported more
frequently in the treatment group (as compared to placebo, all from iPrEx-trial).
Headache (7% vs. 6%)
Syphilis 6% vs. 5%, secondary syphilis (6% vs. 4%)
Abdominal pain (4% versus 2%)
Weight decreased (3% vs, 2%).

The following laboratory abnormalities were reported in these trials.

Creatinine

Phosphorus

AST

ALT

Gradeb

iPrEx Trial

1 (1.1-1.3 x ULN

FTC/TDF
N=125127 (2%)

Placebo
N=124821 (2%)

FTC/TDF
N=157918 (1%)

Placebo
N=154812 (<1%)2-4 (>1.4 x ULN

5 (<1%)

3 (<1%)

2 (<1%)

1 (<1%)

1 (2.5 - <LLN mg/dl

81 (7%)

110 (9%)NRa

NRa

2-4 (<2.5 mg/dl

123 (10%)101 (8%)140 (9%)136 (9%)1 (1.25 - <2.5 x ULN)

175 (14%)175 (14%)20 (1%)

25 (2%)

2-4 (> 2.6 x ULN)

57 (5%)

61 (5%)

10 (<1%)4 (<1%)

1 (1.25 - <2.5 x ULN)

178 (14%)194 (16%)21 (1%)

25 (2%)

2-4 (> 2.6 x ULN)

84 (7%)

84 (7%)

4 (<1%)

6 (<1%)

Partners PrEP Trial

Page 21 of 30

Lamivudine/tenofovir disoproxil fumarate
300mg/300mg Tablets (Macleods
Pharmaceuticals Ltd.), HA514

Haemoglobin

Neutrophils

WHOPAR Part 4

August 2020
Section 6 updated: May 2024

1 (8.5-10 mg/dl)

49 (4%)

62 (5%)

56 (4%)

39 (2%)

2-4 (< 8.4 mg/dl)

13 (1%)

19 (2%)

28 (2%)

39 (2%)

1 (1000-1300/mm3)

23 (2%)

25 (2%)

208 (13%)

13 (10%)2-4 (< 750 mm3)

7 (<1%)

7 (<1%)

73 (5%)

56 (3%)

a. Grade 1 phosphorus was not reported for the Partners PrEP trial
b. Grading is per DAIDS criteria

In addition to the laboratory abnormalities described above, grade 1 proteinuria occurred in 6% of subjects
receiving emtricitabine §/tenofovir disoproxil fumarate in the iPrEx trial. Grades 2-3 proteinuria andglycosuria occurred in less than 1% of subjects treated with emtricitabine*/tenofovir disoproxil fumarate in
the iPrEx trial and PartnersPrEP trial.
Six subjects in the tenofovir-containing arms of the Partners PrEP trial discontinued participation in the study
due to an increase in blood creatinine compared with no discontinuations in the placebo group. One subject
in the emtricitabine§/tenofovir disoproxil arm of the iPrEx trial discontinued from the study due to anincrease in blood creatinine and another due to low phosphorous.
Changes in Bone Mineral Density (BMD)
In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, asubstudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% acrosstotal hip, spine, femoral neck, and trochanter in the emtricitabine§/tenofovir disoproxil fumarate groupcompared with the placebo group, which returned toward baseline after discontinuation of treatment.
Thirteen percent of subjects receiving emtricitabine§/tenofovir disoproxil fumarate vs. 6% of subjects
receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in
1.7% of the emtricitabine§/tenofovir disoproxil fumarate group compared with 1.4% in the placebo group.
No correlation between BMD and fractures was noted (see 5.1 Clinical results). The Partners PrEP trial
found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively). No BMD
evaluations were conducted during this trial.
Description of selected adverse reactions
Renal toxicity
As tenofovir disoproxil may cause renal damage, monitoring of renal function is recommended (see sections
4.4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation.
However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir
disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk
factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased
risk of incomplete recovery of renal function despite
tenofovir disoproxil discontinuation (see section 4.4).
Interaction with didanosine
Co-administration of tenofovir disoproxil and didanosine is not recommended as it results in a 40-60%
increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse
reactions. (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

§

Based on a systematic review it is suggested that emtricitabine and lamivudine are pharmacologically equivalent, andhence clinically interchangeable for therapy of HIV infection. Limited data are also indicative of a similar
pharmacological effect in PrEP. Therefore, herein reference is made also to data obtained with emtricitabine.
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Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an
inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune
disorders (such as Graves’ disease) have also been reported (see section 4.4).
Osteonecrosis
Cases of osteonecrosis have been reported. The frequency of this is unknown (see section 4.4).
Special populations
Paediatric population
Safety data from studies using the combination tablet in patients less than 10 years of age are not available.
In studies with emtricitabine§ in addition to the adverse reactions reported in adults, the following adverse
reactions were observed more frequently in paediatric patients: anaemia was common (9.5%) and skindiscolouration (increased pigmentation) was very common (31.8%).
The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil orlamivudine as single entities were consistent with those observed in clinical studies in adults.
Reductions in bone mineral density (BMD) have been reported with tenofovir disoproxil in paediatricpatients. In HIV-infected adolescents, the BMD Z-scores in subjects who received tenofovir disoproxil werelower than those in subjects who received placebo. In HIV-infected children, the BMD Z-scores in subjects
who switched to tenofovir disoproxil were lower than those in subjects who remained on regimens
containing stavudine or zidovudine.
Elderly
Caution should be exercised since elderly patients are more likely to have decreased renal function.
Co-infection with hepatitis B or C
Limited data on patients co-infected with HIV/HBV or HIV/HCV indicate that the adverse reaction profile ofemtricitabine* and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV was similar tothat observed in patients infected with HIV without co-infection. However, as would be expected, elevations
in AST and ALT occurred more frequently than in the general HIV infected population.
In HIV-negative individuals limited data indicate that the adverse reaction profile of emtricitabine* andtenofovir disoproxil was similar in individuals with and without hepatitis B/C infection.
Exacerbations of hepatitis after discontinuation of treatment
In HBV-infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after
discontinuation of HBV therapy (see section 4.4).
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 to the marketing authorisation holder, or, if available, via thenational reporting system.
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. Health care providers are asked toreport any suspected adverse reactions to the marketing authorisation holder, or, if available, via the national
reporting system.
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Overdose

Symptoms
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), andstandard supportive treatment applied as necessary.
Treatment
Since a negligible amount of lamivudine was removed via (4-hour) haemodialysis, continuous ambulatory
peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous haemodialysis would beclinically beneficial in a lamivudine overdose.
Tenofovir disoproxil can be removed by haemodialysis; the median haemodialysis clearance of tenofovir
disoproxil is 134 ml/minute. The elimination of tenofovir disoproxil by peritoneal dialysis has not beenstudied.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC code: J05AR12
Mechanism of action
Lamivudine, the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue. Tenofovir
disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine
monophosphate.
Lamivudine and tenofovir are phosphorylated by cellular enzymes to form lamivudine triphosphate andtenofovir diphosphate, respectively. Lamivudine triphosphate and tenofovir diphosphate competitively
inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination. Both substances are active against
HIV-1 and HIV-2, as well as against hepatitis B virus.
Pharmacodynamic effects
Antiviral activity in cell culture
Lamivudine
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including
monocytes and (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to
15 microM. against HIV-1 clades A-G and group O viruses
Tenofovir disoproxil
The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T
lymphoblastoid cell lines, primary monocyte/macrophage cells and PBMCs. The EC50 values for tenofovir
were in the range of 0.04-8.5 microM. Tenofovir displayed antiviral activity in cell culture against HIV-1
clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5-2.2 microM).
Resistance in vitro and in vivo
The K65R mutation is selected in vitro when HIV-1 is cultured in the presence of increasing tenofovir
concentrations. It may also emerge in vivo upon virological failure of a treatment regimen including
tenofovir. K65R reduces tenofovir susceptibility in vitro approximately 2-fold, and has been associated witha lack of response to tenofovir-containing regimens. Clinical studies in treatment-experienced patients haveassessed the anti-HIV activity of tenofovir against strains of HIV-1 with thymidine analogue mutations(TAMs), which are not selected for by tenofovir. HIV strains which expressed 3 or more TAMs that included
either the M41L or L210W mutation showed reduced response to tenofovir.
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In many cases when a lamivudine-containing treatment regimen fails (though less often when the treatment
regimen contains a ritonavir-boosted protease inhibitor), the M184V mutation will be selected for at an earlystage. M184V causes high-level resistance to lamivudine (> 300-fold reduced susceptibility). Virus with
M184V replicates less well than does wild-type virus. In vitro data suggest that continuation of lamivudine inan antiretroviral regimen despite the development of M184V might provide residual antiretroviral activity(likely through impaired viral fitness). The clinical relevance of these findings is not established. Therefore,
maintaining lamivudine therapy despite emergence of M184V mutation should be considered only when theactivity of the best available NRTI backbone is significantly compromised.
Cross-resistance conferred by the M184V mutation is limited within the nucleoside/nucleotide inhibitor classof antiretroviral agents. M184V confers full cross-resistance against emtricitabine **. Zidovudine andstavudine maintain their antiretroviral activity against lamivudine-resistant HIV-1. Abacavir maintains its
antiretroviral activity against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V
mutant shows a < 4-fold decrease in susceptibility to didanosine; the clinical significance of this is unknown.
Clinical efficacy and safety
Several clinical studies have confirmed the efficacy of the individual components of this fixed dosecombination product. Lamivudine and tenofovir disoproxil were used as single entities in different
combination regimens. No clinical studies have been conducted.with the combination lamivudine andtenofovir disoproxil .
When tenofovir and lamivudine were combined with efavirenz in treatment-naïve patients with HIV-1, theproportion of patients (ITT) with HIV-RNA < 50 copies/ml were 76.3% and 67.8% at 48 and 144 weeks,
respectively.
Pre-exposure Prophylaxis
In a primary prevention trial (iPrEX), designed to evaluate the safety and efficacy of once-daily oral
tenofovir disoproxil-emtricitabine** compared with placebo for the prevention of HIV acquisition among
men who have sex with men and among transgender women both having evidence of high risk behaviour for
HIV-1 infection, use of pre-exposure prophylaxis with a median follow-up time of 1.2 years was associatedwith reduced risk of new HIV infection in both intention-to-treat analysis (HR: 0.53, 95% CI 0.36–0.78,
p=0.001) and modified intention-to-treat analysis (HR: 0.56, 95% CI 0.37–0.85, p<0.001).
In the Partners PrEP trial, conducted in serodiscordant heterosexual couples to evaluate the efficacy andsafety of emtricitabine**/tenofovir disoproxil versus placebo, in preventing HIV-1 acquisition by theuninfected partner, the risk reduction for emtricitabine**/tenofovir disoproxil relative to placebo was 75%(HR: 0.25, 95% CI: 0.55-0.87, p=0.005) following 7827 person-years of follow-up.
In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction
appeared to be the greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly
correlated with adherence.
5.2

Pharmacokinetic properties<Product-specific table on absorption characteristics to be created by person in charge of the specific
WHOPAR. Consult BE-contribution for specific data and see text models in “HELP >Lamivudine

Tenofovir disoproxil

GeneralTenofovir disoproxil is a water-soluble
ester prodrug, which is rapidly converted in**

Based on a systematic review it is suggested that emtricitabine and lamivudine are pharmacologically equivalent, andhence clinically interchangeable for therapy of HIV infection. Limited data are also indicative of a similar
pharmacological effect in PrEP. Therefore, herein reference is made also to data obtained with emtricitabine.
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vivo to tenofovir. Tenofovir is converted
intracellularly to tenofovir monophosphate
and to the active component, tenofovir
diphosphate.
Absorption
Absolute bioavailability

NA

NA

Oral bioavailability

80-85%

25%

Food effectCo-administration of lamivudine withfood results in a delay of Tmax and alower Cmax (decreased by 47%).
However, the extent (based on the AUC)
of lamivudine absorbed is not influenced.

1.3 L/kg

800 ml/kg

Distribution
Volume of distribution(mean)
Plasma protein binding invitro
Tissue distribution< 36% serum albumin in vitro
mean CSF:serum ratio=0.12.
The true extent of penetration or relationshipwith any clinical efficacy is unknown.

AUC(0-∞)

Cmax

Tmax

Light
meal

No
significant
effectNosignificant
effectNosignificant
effect

High
fat:

40%↑

14%↑

1h↑

< 0.7 % (serum protein binding < 7.2%)
Well distributed, with highest
concentrations in kidney and liver.

Metabolism
Only minor route (< 10%)In vitro studies have determined that neither
tenofovir disoproxil nor tenofovir is a
substrate for the CYP450 enzymes.

None

Tenofovir

Active metabolite(s)Elimination
Elimination half life

5-7 hTenofovir: 12 to 18 h

22 h for intracellular lamivudine
triphosphate

Tenofovir diphosphate: 10h in intracellular
activated resting peripheral bloodmononuclear cells and 50 hours in resting
peripheral blood mononuclear cells.

Mean systemic clearance(Cl/F)

0.32 L/h/kg

0.23 L/h/kg% of dose excreted in urine> 70% [Predominantly cleared
unchanged]

70-80% as unchanged drug

% of dose excreted in faeces

NA

NA

Pharmacokinetic linearity

Linear pharmacokinetics

Linear pharmacokinetics(dose range 75 to 600 mg)

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Drug interactions (in vitro)
Transporters

OCT (organic cationic transporters)

Metabolizing enzymes

Substrate of hOAT 1, hOAT3 and MRP 4.
No significant inhibition of CYP3A4,CYP2D6, CYP2C9, CYP2E1, or
CYP1A1/2

Special populations
ChildrenTenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg
was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg.
Pharmacokinetic studies have not been performed with tenofovir disoproxil 245 mg tablets in children under
12 years or with renal impairment.
Limited data are available in adolescents receiving a daily dose of 300 mg of lamivudine. Pharmacokinetic
parameters are comparable to those reported in adults.
Elderly
Pharmacokinetic data for tenofovir and lamivudine in subjects aged over 65 years are limited.
Renal impairment[HA514 trade name] is not recommended for use in patients with a creatinine clearance < 50 ml/min, as
appropriate dose adjustments are not possible.
Pharmacokinetic parameters of tenofovir disoproxil were determined following administration of a single
dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees
of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when
CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with
CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir
exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to respectively 3,064(30%) ng·h/ml, 6,009 (42%) ng·h/ml and 15,985 (45%) ng·h/ml in patients with mild, moderate and severe
renal impairment. The dosing recommendations in patients with renal impairment, with increased dosinginterval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients withrenal impairment compared with patients with normal renal function. The clinical implications of this are
unknown.
In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between
dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml
and a mean AUC0-48h of 42,857 ng·h/ml. It is recommended that the dosing interval for tenofovir disoproxil
245 mg (as fumarate) is modified in adult patients with creatinine clearance < 50 ml/min or in patients whoalready have ESRD and require dialysis.
The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min andin patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.
Hepatic impairment
The pharmacokinetics of tenofovir following a 245 mg single dose of tenofovir disoproxil have been studied
in non-HIV infected subjects with moderate to severe (ChildPugh B to C) hepatic impairment. There were no
substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with
unimpaired subjects.
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GenderThere is no evidence that a dose adjustment of tenofovir disoproxil or lamivudine would be required basedon the effects of gender on PK parameters.
Ethnicity
There is no evidence that a dose adjustment of tenofovir disoproxil or lamivudine would be required basedon the effects of ethnicity on PK parameters.
5.3

Preclinical safety data

Tenofovir disoproxil
Preclinical studies in rats, dogs and monkeys revealed target-organ effects on gastrointestinal tract, kidney,bone and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia(monkeys) and reduced bone mineral density (rats and dogs). Findings in the rat and monkey studies
indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential
secondary reduction in bone mineral density. However, no conclusion could be drawn on the mechanism(s)underlying these toxicities.
Reproductive studies were conducted in rats and rabbits. There were no effects on mating or fertility
parameters or on any pregnancy or fetal parameter. There were no gross fetal alterations of soft or skeletal
tissues. Tenofovir disoproxil reduced the viability index and weight of pups in peri-post-natal toxicity
studies.
Genotoxicity studies have shown that tenofovir disoproxil was negative in the in vivo mouse bone marrow
micronucleus assay but was positive for inducing forward mutations in the in vitro L5178Y mouse
lymphoma cell assay in the presence or absence of S9 metabolic activation. Tenofovir disoproxil was
positive in the Ames test (strain TA 1535) in two out of three studies, once in the presence of S9 mix (6.2- to
6.8-fold increase) and once without S9 mix. Tenofovir disoproxil was also weakly positive in an in vivo/in
vitro unscheduled DNA synthesis test in primary rat hepatocytes.
Tenofovir disoproxil did not show any carcinogenic potential in a long-term oral carcinogenicity study inrats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumours,
considered likely related to high local concentration of tenofovir disoproxil in the gastrointestinal tract at adose of 600 mg/kg/day. While the mechanism of tumour formation is uncertain, the findings are unlikely to
be of relevance to humans.
Lamivudine
Administration of lamivudine in animal toxicity studies at high doses was not associated with any majororgan toxicity.
Lamivudine was not mutagenic in bacterial tests, but showed activity in an in vitro cytogenetic assay and themouse lymphoma assay. Lamivudine was not genotoxic in vitro at doses that gave plasma concentrations
around 40–50 times higher than the expected clinical plasma levels. As the in vitro mutagenic activity oflamivudine could not be confirmed in vivo, it is concluded that lamivudine should not represent a genotoxic
hazard to patients undergoing treatment.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential
relevant for humans.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Tablet core:
Croscarmellose sodium
Magnesium stearate
Microcrystalline cellulose
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Film coat:
Hypromellose
Lactose monohydrate
Titanium dioxide
Triacetin
6.2 Incompatibilities
Not applicable
6.3 Shelf life
24 months (Blister pack)36 months (HDPE bottle)
6.4 Special precautions for storage
HDPE bottles: Store below 30°C, in a dry place protected from light.
Alu-Alu blisters: Store below 25°C, in a dry place protected from light.
6.5 Nature and contents of container-Round, white HDPE bottle with Continuous Thread PP closure and silica gel sachet. Pack size: 30 tablets.
-Blister pack of Alu foil and a cold form laminate of OPA/Alu/PVC containing 10 tablets. 10 blisters per
carton.
6.6 Instructions for use and handling and disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.

7.

SUPPLIER

Macleods Pharmaceuticals Limited
304, Atlanta Arcade,
Marol Church road,
Andheri (East),
Mumbai – 400 059, India.
Tel: +91-22-66762800
Fax: +91 -22-29256229
Email: sjadhav@macleodspharma.com
vijay@macleodspharma.com

8.

WHO REFERENCE NUMBER (WHO Prequalification Programme)

HA514

9.

DATE OF PREQUALIFICATION

10 April 2014

10.

DATE OF REVISION OF THE TEXT

August 2020
Section 6 was updated in May 2024

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ReferencesWHO. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure
prophylaxis and recommendations on early infant diagnosis of HIV. Interim guidance, 2018, available athttps://www.who.int/hiv/pub/guidelines/ARV2018update/en/WHO. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2016
update. Available at https://www.who.int/hiv/pub/toolkits/keypopulations-2016-update/en/WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.
Recommendations for a public health approach. Second edition, 2016. Available at:https://www.who.int/hiv/pub/arv/arv-2016/en/
WHO Policy Brief Pre-exposure prophylaxis (PrEP), 2015. Available at:
http://apps.who.int/iris/bitstream/10665/197906/1/WHO_HIV_2015.48_eng.pdf?ua=1
WHO Technical Brief Event-driven oral pre-exposure prophylaxis to prevent HIV for men who have sex
with men: Update to WHO’s recommendation on oral PrEP, 2019. Available at:https://apps.who.int/iris/bitstream/handle/10665/325955/WHO-CDS-HIV-19.8-eng.pdf?ua=1
Ford N, Shubber Z, Hill A, Vitoria M, Doherty M, Mills EJ, Gray A. Comparative efficacy of Lamivudine
and emtricitabine: a systematic review and meta-analysis of randomized trials. PLoS One. 2013;8(11):e79981.
European SmPC of Epivir available at:https://www.ema.europa.eu/en/documents/product-information/epivir-epar-product-information_en.pdf
European SmPC of Viread available at:https://www.ema.europa.eu/en/documents/product-information/viread-epar-product-information_en.pdf
CIMDUO, US prescribing information, available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022141s000lbl.pdf
University of Liverpool, HIV Drug interactions, available at: http://www.hiv-druginteractions.org
All weblinks last accessed in August 2020.

Detailed information on this medicine is available on the World Health Organization (WHO)website: https://extranet.who.int/prequal/

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