Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: MILUTIN  
Dosage form and strength: Film coated tablet and 50/300/300 mg  
PROFESSIONAL INFORMATION FOR LUVIGEN  
SCHEDULING STATUS  
S4  
WARNING:  
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL  
CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE  
OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE SECTION 4.4).  
LUVIGEN IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS  
(HBV) INFECTION. SAFETY AND EFFICACY OF LUVIGEN HAS NOT BEEN ESTABLISHED IN  
PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF  
HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HBV  
AND HIV AND HAVE DISCONTINUED THE COMBINATION TABLET. HEPATIC FUNCTION  
SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-  
UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE LUVIGEN AND  
ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS  
B THERAPY MAY BE WARRANTED (SEE SECTION 4.4).  
1 NAME OF THE MEDICINE  
LUVIGEN film coated tablet  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film coated tablet contains dolutegravir sodium equivalent to dolutegravir 50 mg,  
lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg.  
Contains sugar (140,4 mg mannitol per tablet).  
For full list of excipients, see section 6.1.  
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3 PHARMACEUTICAL FORM  
Orange coloured, modified capsule shaped, biconvex film coated tablet debossed with ‘H’ on  
one side, ‘D’ and ‘17’ on the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
LUVIGEN is indicated for the treatment of HIV-1 infection in adults aged 18 years and older.  
4.2 Posology and method of administration  
Posology  
Therapy should be initiated by a medical practitioner experienced in the management of HIV  
infection.  
Adults:  
The dose of LUVIGEN is one tablet taken orally, once daily, without regard to food.  
Paediatrics:  
LUVIGEN is not recommended for use in patients younger than 18 years of age.  
Renal impairment: Significantly increased exposure occurred when tenofovir, as in LUVIGEN,  
was administered to patients with renal impairment (see section 4.3).  
The pharmacokinetics of tenofovir, as in LUVIGEN, have not been evaluated in non-  
haemodialysis patients with creatinine clearance < 80 ml/min); therefore, no dosing  
recommendations is available for these patients.  
LUVIGEN is not suitable for use in patients with renal impairment with creatinine clearance less  
than 80 ml/min.  
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Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir  
should be given to patients taking LUVIGEN.  
Isoniazid decreases dolutegravir plasma concentrations. A supplementary dose of dolutegravir  
should be given to patients taking LUVIGEN.  
Method of administration  
LUVIGEN is a coated tablet, should not be chewed as it may take them to taste very  
unpleasant. LUVIGEN should not be broken because the coating is intended to ensure a  
prolonged release.  
4.3 Contraindications  
•
LUVIGEN tablets are contraindicated in patients with known hypersensitivity to lamivudine,  
tenofovir or dolutegravir or to any of the components of the tablets.  
Impaired renal failure.  
•
•
•
•
•
•
•
•
•
Pregnancy and lactation (see section 4.6).  
Women of child-bearing age not using highly effective contraception.  
Concomitant use with adefovir dipivoxil.  
Co-administration with dofetilide and pilsicainide.  
Co-administration with didanosine.  
Co-administration with metformin.  
Patients younger than 18 years of age.  
Moderate and severe hepatic impairment.  
4.4 Special warnings and precautions for use  
Safety and efficacy of the individual active ingredients in various antiretroviral combination  
regimens with similar dosages as contained in LUVIGEN have been established in clinical  
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studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug  
combination as in LUVIGEN for the treatment of HIV have not been established in clinical  
studies.  
The complete professional information of the other medicines used in combination should be  
consulted before initiation of therapy.  
Metabolic abnormalities  
Combination antiretroviral therapy, including LUVIGEN has been associated with metabolic  
abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance,  
hyperglycaemia and hyperlactataemia.  
Lipodystrophy  
Combination antiretroviral therapy, including LUVIGEN, has also been associated with the  
redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement  
(buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients.  
A higher risk of lipodystrophy has been associated with individual factors such as older age and  
with medicine related factors such as longer duration of antiretroviral treatment and associated  
metabolic disturbances. Clinical examination should include evaluation for physical signs of fat  
redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid  
disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy  
should have a thorough cardiovascular risk assessment.  
Immune reconstitution inflammatory syndrome  
Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response  
resulting from the rapid restoration of pathogen-specific immune responses to pre-existing  
antigens combined with immune dysregulation, which occurs shortly after starting combination  
Anti-Retroviral Therapy (cART), an inflammatory reaction to asymptomatic or residual  
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opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of  
symptoms. Typically, such reaction presents by paradoxical deterioration of opportunistic  
infections being treated or with unmasking of an asymptomatic opportunistic disease, often with  
an atypical inflammatory presentation. IRIS usually develops within the first few weeks or three  
months of initiation of ART and occurs more commonly in patients with low CD4 counts.  
Common examples of IRIS reactions to opportunistic diseases are tuberculosis, atypical  
mycobacterial infections, cytomegalovirus retinitis, pneumocystis jirovecii (carinii) pneumonia  
and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be  
instituted or continued and ART continued when necessary. Inflammatory manifestations  
generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is  
only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as  
Graves' disease, Guillain-Barre Syndrome, Polymyositis) have also been reported as IRIS  
reactions; however, the reported time to onset is more variable and these events can occur  
many months after initiation of treatment.  
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), including components of LUVIGEN.  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint  
stiffness or difficulty in movement.  
Opportunistic infections  
Patients receiving LUVIGEN may continue to develop opportunistic infections and other  
complications of HIV infection, and therefore should remain under close clinical observation by  
doctors experienced in the treatment of patients with HIV associated diseases.  
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The risk of HIV-transmission to others  
Patients should be advised that treatment with LUVIGEN, have not been proven to prevent the  
risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate  
precautions must continue to be used.  
Lactic acidosis/severe hepatomegaly with steatosis  
Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been  
reported with the use of nucleoside analogues, such as in LUVIGEN. Early symptoms  
(symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and  
abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms  
(rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic  
acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal  
failure.  
Lactic acidosis generally occurs after a few or several months of treatment. Treatment with  
nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia  
and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase  
levels.  
Suspicious biochemical features include mild raised transaminases, raised lactate  
dehydrogenase (LOH) and/or creatine kinase.  
In patients with suspicious symptoms or biochemistry, measure the venous lactate level  
(normal < 2 mmol/ℓ) and respond as follows:  
-
-
Lactate 2-5 mmol/ℓ: monitor regularly, and be alert for clinical signs.  
Lactate 5-10 mmol/ℓ without symptoms: monitor closely.  
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-
Lactate 5-10 mmol/ℓ with symptoms: STOP all therapy. Exclude other causes (e.g.  
sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma).  
-
Lactate > 10 mmol/ℓ: STOP all therapy (80 % mortality in case studies).  
The above lactate values may not be applicable to paediatric patients.  
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased  
anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a  
raised lactate level.  
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been  
reported with the use of LUVIGEN alone or in combination, in the treatment of HIV infection.  
Most cases were women.  
Caution should be exercised when administering LUVIGEN to patients with known risk factors  
for liver disease.  
Treatment with LUVIGEN should be suspended in any patient who develops clinical or  
laboratory findings suggestive of lactic acidosis or hepatotoxicity. Caution should be exercised  
when administering nucleoside analogues as contained in LUVIGEN to any patient (particularly  
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and  
hepatic steatosis (including certain medicines and alcohol). Patients co-infected with hepatitis C  
and treated with alpha interferon and ribavirin may constitute a special risk. Patients at  
increased risk should be followed closely. However, cases have also been reported in patients  
with no known risk factors.  
Patients at increased risk should be followed closely.  
There are no study results demonstrating the effect of LUVIGEN on clinical progression of HIV-  
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1.  
Mitochondrial dysfunction  
Nucleoside and nucleotide analogues as contained in LUVIGEN have been demonstrated in  
vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports  
of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to  
nucleoside analogues. The main adverse events reported are haematological disorders  
(anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipidaemia). These events  
are often transitory. Some late-onset neurological disorders have been reported (hypertonia,  
convulsion, abnormal behaviour). Whether the neurological disorders are transient or  
permanent is unknown.  
Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative  
children, should have clinical and laboratory follow-up and should be fully investigated for  
possible mitochondrial dysfunction in case of relevant signs or symptoms.  
Pancreatitis  
Pancreatitis has been observed in some patients receiving lamivudine, as in LUVIGEN. It is  
unclear whether this was due to lamivudine or to underlying HIV disease. Pancreatitis must be  
considered whenever a patient develops abdominal pain, nausea, vomiting or elevated  
biochemical markers. Discontinue use of LUVIGEN until diagnosis of pancreatitis is excluded.  
Patients with moderate to severe renal impairment  
In patients with moderate to severe renal impairment, the terminal half-life of LUVIGEN is  
increased due to decreased clearance. The dose of LUVIGEN should therefore be adjusted*  
(see section 4.2).  
Liver disease  
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Use of LUVIGEN can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic  
steatosis).  
The safety and efficacy of LUVIGEN has 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 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.  
Renal impairment  
LUVIGEN is a combination product and the dose of the individual components cannot be  
altered. Tenofovir and lamivudine are principally eliminated by the kidneys.  
LUVIGEN is not recommended for patients with creatinine clearance < 80 ml/min or patients  
who require haemodialysis. Renal impairment, including cases of acute renal failure and  
Fanconi syndrome (renal tubular injury with severe hypophosphataemia) has been reported  
with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal  
function (serum creatinine and serum phosphate) is therefore recommended before taking  
LUVIGEN.  
Renal function  
Since LUVIGEN is primarily eliminated by the kidneys, co-administration of LUVIGEN with  
medicines that reduce renal function or compete for active tubular secretion may increase  
serum concentrations of LUVIGEN and/or increase the concentrations of other renally  
eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil,  
cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.  
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with  
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impaired renal function (creatinine clearance < 80 ml/min).  
Renal monitoring  
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed  
in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also  
monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and  
then every three months. In patients at risk for renal impairment, including patients who have  
previously experienced renal events while receiving adefovir dipivoxil, consideration should be  
given to more frequent monitoring of renal function.  
Co-administration and risk of renal toxicity  
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a  
nephrotoxic medicine (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir,  
pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil  
fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly  
for changes in serum creatinine phosphorous.  
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines  
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 medicine).  
These renal transport proteins may be responsible for tubular secretion and in part, renal  
elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicines,  
which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or  
MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant  
use of these medicines which are secreted by the same renal pathway is not recommended,  
but if such use is unavoidable, renal function should be monitored weekly.  
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K65R mutation  
LUVIGEN should be avoided in antiretroviral experienced patients with HIV-1 harbouring the  
K65R mutation.  
Bone mineral density  
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline are  
significantly greater with tenofovir disoproxil fumarate as contained in LUVIGEN. Decreases in  
bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are  
reported. If bone abnormalities are suspected then appropriate consultation should be  
obtained. Bone monitoring should be considered for HIV infected patients who have a history of  
pathologic bone fracture or are at risk of osteopenia.  
LUVIGEN may cause a reduction in bone mineral density. The effects of tenofovir disoproxil  
fumarate-associated changes in bone mineral density on long-term bone health and future  
fracture risk are currently unknown.  
Bone monitoring should be considered for HIV infected patients who have a history of  
pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation  
with calcium and vitamin D was not studied, such supplementation may be beneficial for all  
patients. If bone abnormalities are suspected then appropriate consultation should be obtained.  
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal  
renal tubulopathy.  
Patients with HIV and hepatitis B or C virus co-infection  
LUVIGEN is not indicated for the treatment of chronic HBV infection. The safety and efficacy of  
LUVIGEN has not been established for the treatment of patients co-infected with HBV and HIV.  
Patients with chronic hepatitis B or C and treated with antiretroviral therapy such LUVIGEN are  
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at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical  
practitioners should refer to current HIV treatment guidelines for the optimal management of  
HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant  
antiviral therapy for hepatitis B or C, please refer also to the relevant professional information  
for these medicines.  
Exacerbations of hepatitis  
Flares on treatment:  
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised  
by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase  
in some patients. In patients with compensated liver disease, these increases in serum 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 exacerbations of hepatitis have been reported in patients after the discontinuation of  
hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA,  
and the majority appears to be self-limited. However, severe exacerbations, including fatalities,  
have been 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 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 may lead to hepatic decompensation. Liver flares are  
especially serious, and sometimes fatal in patients with decompensated liver disease.  
Hypersensitivity reactions  
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Hypersensitivity reactions may occur with the use of LUVIGEN. LUVIGEN and other suspect  
agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions  
develop (including, but not limited to, severe rash or rash accompanied by fever, general  
malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema,  
hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be  
monitored. Delay in stopping treatment with LUVIGEN or other suspect active substances after  
the onset of hypersensitivity may result in a life-threatening allergic reaction.  
Use in elderly  
Clinical studies did not include sufficient numbers of patients aged 65 and over to determine  
whether they respond differently from younger patients.  
Paediatric population  
Safety and effectiveness in paediatric patients and patients < 18 years of age have not been  
established.  
4.5 Interaction with other medicines and other forms of interaction  
Renally eliminated medicines  
Tenofovir, as in LUVIGEN, is primarily excreted by the kidneys by a combination of glomerular  
filtration and active tubular secretion. Co-administration of LUVIGEN with medicines that are  
eliminated by active tubular secretion may increase serum concentrations of either tenofovir or  
the co-administered medicines due to competition for this elimination pathway. Medicines that  
decrease renal function may also increase serum concentrations of tenofovir, as in LUVIGEN.  
Tenofovir has been evaluated in healthy volunteers in combination with abacavir, adefovir  
dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine,  
lopinavir/ritonavir, methadone, oral contraceptives and ribavirin. Tables 1 and 2 summarise  
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pharmacokinetic effects of co-administered medicine on tenofovir pharmacokinetics and effects  
of tenofovir on the pharmacokinetics of co-administered medicine.  
When administered with multiple doses of tenofovir, the Cmax and AUC of didanosine 400 mg  
increased significantly. The mechanism of this interaction is unknown.  
When didanosine 250 mg enteric-coated capsules were administered with tenofovir, systemic  
exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules  
alone under fasted conditions.  
Table 1:  
Medicine Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence  
of co-administered medicines:  
Co- administered  
Medicine  
Dose of Co-  
administered  
Medicine (mg)  
N
% Change of Tenofovir Pharmacokinetic  
Parameters2 (90 % Cl)  
Cmax  
AUC  
Cmin  
Abacavir  
300 once  
10 once  
8
↔
↔
NC  
↔
Adefovir dipivoxil  
Atazanavir  
22  
33  
↔
↔
400 once daily  
x 14 days  
400 once  
↑ 14  
↑ 24  
↑ 22  
(↑ 8 to ↑ 20)  
↔
(↑ 21 to ↑ 28)  
↔
(↑ 15 to ↑ 30)  
↔
Didanosine  
(enteric-coated)  
Didanosine  
(buffered)  
25  
14  
250 or 400  
once daily x 7  
days  
↔
↔
↔
Efavirenz  
600 once daily  
x 14 days  
29  
17  
↔
↔
↔
↔
↔
↔
↔
↔
↔
↔
Emtricitabine  
Indinavir  
200 once daily  
x 7 days  
800 three times 13  
daily x 7 days  
↑ 14  
(↓ 3 to ↑ 33)  
↔
Lamivudine  
150 twice daily  
x 7 days  
15  
Lopinavir/Ritonavir 400/100 twice  
daily x 14 days  
24  
↔
↑ 32  
↑ 51  
(↑ 25 to ↑ 38)  
(↑ 37 to ↑ 66)  
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1. Patients received tenofovir DF 300 mg once daily  
2. Increase = ↑; Decrease = ↓; No effect = ↔; NC = Not calculated  
Following multiple dosing to HIV-negative subjects receiving either chronic methadone  
maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir  
pharmacokinetics were similar to those observed in previous studies, indicating a lack of  
clinically significant medicines interactions between these medicines and tenofovir disoproxil  
fumarate.  
Table 2:  
Medicine Interactions: Changes in Pharmacokinetic Parameters for Co-administered Medicines  
in the Presence of Tenofovir  
Co- administered  
Medicine  
Dose of Co-  
administered Medicine  
(mg)  
N
% Change of Tenofovir  
Pharmacokinetic Parameters1  
(90 % Cl)  
Cmax  
↑ 122  
AUC  
Cmin  
Abacavir  
300 once  
8
↔
NA  
(↑ 1 to ↑  
26)  
Adefovir dipivoxil  
Efavirenz  
10 once  
22 ↔  
↔
↔
NA  
600 mg once daily x 14  
days  
30 ↔  
↔
Emtricitabine  
Indinavir  
200 mg once daily x 7  
days  
17 ↔  
↔
↔
↔
↔
800 mg three times  
daily x 7 days  
12 ↑ 14  
(↓ 3 to ↑  
33)  
15 ↔  
Lamivudine  
150 mg twice daily x 7  
days  
↔
↔
↔
↔
↔
↔
Lopinavir/Ritonavir  
Methadone2  
400/100 twice daily x  
14 days  
21 ↔  
40-110 once daily x 14  
days3  
13 ↔  
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Oral  
Ethinyl  
20 ↔  
↔
↔
contraceptives4  
oestradiol/Norgestimate  
(Ortho-Tricyclen®  
Once daily x 7 days  
600 once  
Ribavirin  
Ritonavir  
22 ↔  
↔
↔
NA  
Lopinavir/Ritonavir  
400/100 twice daily x  
14 days  
24 ↔  
↔
Atazanavir5  
Atazanavir5  
400 once daily x 14  
days  
29 ↔  
↔
↔
Atazanavir/Ritonavir  
300/100 once daily x 42  
days  
10 ↑ 28  
↑ 25  
↑ 236  
(↑ 50 to ↑  
(↑ 42 to ↑  
(↑ 46 to ↑  
10)  
5)  
3)  
Saquinavir/Ritonavir 1000/100 twice daily x  
14 days  
35 ↔  
↔
↑ 23  
(↑ 16 to ↑  
30)  
1. Increase = ↑; Decrease = ↓; No effect = ↔; NA = Not applicable  
2. R-(active), S- and total methadone exposures were equivalent when dosed alone or with  
tenofovir as tenofovir disoproxil fumarate 300 mg  
3. Individual subjects were maintained on their stable methadone dose. No pharmacodynamic  
alterations (opiate toxicity or withdrawal signs or symptoms) were reported  
4. Ethinyl oestradiol and 17-deacetyl norgestimate (pharmacologically active metabolite)  
exposures were equivalent when dosed alone or with tenofovir as tenofovir DF 300 mg  
5. REYATAZ US Prescribing Information (Bristol-Myers Squibb)  
6. In HIV-infected patients, addition of tenofovir disoproxil fumarate to atazanavir 300 mg plus  
ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2,3- and 4-fold higher  
than the respective values observed for atazanavir 400 mg when given alone  
Lamivudine  
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein  
binding and almost complete renal clearance.  
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Zidovudine plasma levels are not significantly altered when co-administered with lamivudine.  
Zidovudine has no effect on the pharmacokinetics of lamivudine.  
Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines  
are used concurrently. Lamivudine is therefore not recommended to be used in combination  
with zalcitabine.  
Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in  
lamivudine plasma levels. However, unless the patient has renal impairment, no dosage  
adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of  
co-trimoxazole. The possibility of interactions with other medicines administered concurrently  
should be considered, particularly when the main route is renal.  
No interaction studies have been conducted using LUVIGEN. As LUVIGEN contains tenofovir  
disoproxil fumarate and lamivudine, any interactions that have been identified with these  
individual medicines may occur with LUVIGEN. Important interaction information for LUVIGEN  
is summarised in Tables 1, 2 and 3. The medicine interactions described are based on studies  
conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines, or are  
potential medicine interactions. While the tables include potentially significant interactions, they  
are not all inclusive. Based on the results of in vitro experiments and the known elimination  
pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with  
other medicines is low.  
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in  
lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the  
patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/  
zidovudine combination in patients with renal impairment should be carefully assessed.  
Table 3:  
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Co- administered  
Medicine  
% Change of Tenofovir Pharmacokinetic Parameters1 (90 %  
Cl)  
Cmax  
AUC  
Cmin  
Zidovudine  
↑ 28  
↑
↑ 13  
NA  
↔
NA  
NA  
↔
Trimethoprim +  
Cotrimoxazole  
↔
Atazanavir/Ritonavir  
Lopinavir/Ritonavir  
Darunavir/Ritonavir  
NR  
NR  
NR  
NR  
NR  
NR  
NR  
NR  
NR  
Increase = ↑; No effect = ↔; NA = Not applicable; NR = Not recommended  
Dolutegravir  
Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir  
should be given to patients taking LUVIGEN.  
There is evidence that the concentration of isoniazid is increased by dolutegravir, as contained  
in LUVIGEN.  
Effect of LUVIGEN on the pharmacokinetics of other medicines:  
In vitro, LUVIGEN demonstrated no direct, or weak inhibition (IC50 > 50 µM) of the cytochrome  
P450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A,  
uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp,  
BCRP, OATP1B1, OATP1B3, OCT1 or MRP2.  
In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not  
have an effect on midazolam, a CYP3A4 probe. Based on these data, LUVIGEN is not  
expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or  
transporters (e.g. reverse transcriptase and protease inhibitors, opioid analgesics,  
antidepressants, statins, azole antifungals (such as fluconazole, itraconazole, clotrimazole),  
proton pump inhibitors (such as esomeprazole, lansoprazole, omeprazole), anti-erectile  
dysfunction medicines (such as sildenafil, tadalafil, vardenafil), aciclovir, valaciclovir, sitagliptin,  
adefovir).  
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Dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following:  
tenofovir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir,  
rilpivirine, telaprevir and oral contraceptives containing norgestimate and ethinyl estradiol.  
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2). Based on this  
observation, LUVIGEN may increase plasma concentrations of medicines in which excretion is  
dependent upon OCT2 (dofetilide, metformin) (see table 4).  
Effect of other medicines on the pharmacokinetics of LUVIGEN:  
LUVIGEN, is eliminated mainly through metabolism by UGT1A1. LUVIGEN is also a substrate  
of UGT1A3, UGT1A9, CYP3A4, Pgp and BCRP; therefore, medicines that induce those  
enzymes may theoretically decrease dolutegravir plasma concentration and reduce the  
therapeutic effect of LUVIGEN.  
Co-administration of LUVIGEN and other medicines that inhibit UGT1A1, UGT1A3, UGT1A9,  
CYP3A4, and/or Pgp may increase dolutegravir plasma concentration (see table 4).  
Efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir each reduced the  
plasma concentrations of dolutegravir significantly and require LUVIGEN dose adjustment to 50  
mg twice daily.  
Etravirine also reduced plasma concentrations, but the effect of etravirine was mitigated by co-  
administration of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to  
be mitigated by atazanavir/ritonavir. Therefore no LUVIGEN dose adjustment is necessary  
when co-administered with etravirine and either lopinavir/ritonavir, darunavir/ritonavir or  
atazanavir/ritonavir. Another inducer, fosamprenavir in combination with ritonavir decreased  
plasma concentrations of dolutegravir but does not require a dosage adjustment of LUVIGEN.  
Caution is warranted and clinical monitoring is recommended when these combinations are  
given in INI-resistant patients (see table 4: Medicine Interactions – HIV-1 Antiviral Medicines).  
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A interaction study with the UGT1A1 inhibitor, atazanavir, did not result in a clinically  
meaningful increase in the plasma concentrations of dolutegravir. Tenofovir, ritonavir,  
lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, boceprevir, telaprevir, prednisone, rifabutin and  
omeprazole had no or a minimal effect on dolutegravir pharmacokinetics, therefore no  
LUVIGEN dose adjustment is required when co-administered with these medicines.  
Table 4: Medicine interactions  
Concomitant  
Effect on  
Clinical Comment  
Medicine Class:  
Medicine Name  
Concentration of  
LUVIGEN or  
Concomitant  
Medicine  
HIV-1 Antiviral Medicines  
Non-nucleoside Reverse Dolutegravir ↓  
Etravirine decreased dolutegravir plasma  
concentration, which may result in loss of  
virologic response and possible resistance  
to dolutegravir. LUVIGEN should not be  
used with etravirine without co-  
Transcriptase Inhibitor:  
Etravirine (ETR)  
AUC ↓ 71 %  
Cmax ↓ 52 %  
CƮ ↓ 88 %  
ETR ↔  
administration of atazanavir/ritonavir,  
darunavir/ritonavir or lopinavir/ritonavir.  
Efavirenz decreased dolutegravir plasma  
concentrations.  
Non-nucleoside Reverse Dolutegravir ↓  
Transcriptase Inhibitor:  
Efavirenz (EFV)  
AUC ↓ 57 %  
Cmax ↓ 39 %  
CƮ ↓ 75 %  
EFV ↔  
The recommended dose of LUVIGEN is 50  
mg twice daily when co-administered with  
efavirenz. Alternative combinations that do  
not include efavirenz should be used  
where possible in INI-resistant patients.  
Co-administration with nevirapine has the  
potential to decrease dolutegravir plasma  
concentration due to enzyme induction and  
has not been studied. Effect of nevirapine  
on dolutegravir exposure is likely similar to  
or less than that of efavirenz. The  
Non-nucleoside Reverse Dolutegravir ↓  
Transcriptase Inhibitor:  
Nevirapine  
recommended dose of LUVIGEN is 50 mg  
twice daily when co-administered with  
nevirapine. Alternative combinations that  
do not include nevirapine should be used  
where possible in INI-resistant patients.  
Atazanavir increased dolutegravir plasma  
concentration. No dose adjustment is  
necessary.  
Protease Inhibitor:  
Atazanavir (ATV)  
Dolutegravir ↑  
AUC ↑ 91 %  
Cmax ↑ 49 %  
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CƮ ↑ 180 %  
ATV ↔  
Protease Inhibitor:  
Atazanavir/ritonavir  
(ATV + RTV)  
Dolutegravir ↑  
AUC ↑ 62 %  
Cmax ↑ 33 %  
CƮ ↑ 121 %  
ATV ↔  
Atazanavir/ritonavir increased dolutegravir  
plasma concentration. No dose adjustment  
is necessary.  
RTV ↔  
Protease Inhibitor:  
Tipranavir/ritonavir  
(TPV + RTV)  
Dolutegravir ↓  
AUC ↓ 59 %  
Cmax ↓ 47 %  
CƮ ↓ 76 %  
TPV ↔  
Tipranavir/ritonavir decreases dolutegravir  
concentrations. The recommended dose of  
LUVIGEN is 50 mg twice daily when co-  
administered with tipranavir/ritonavir.  
Alternative combinations that do not  
include tipranavir/ritonavir should be used  
where possible in INI resistant patients.  
Fosamprenavir/ritonavir decreases  
dolutegravir concentrations, but based on  
limited data, did not result in decreased  
efficacy in Phase Ill studies. No dose  
adjustment is necessary in INl-naive  
patients. Alternative combinations that do  
not include fosamprenavir/ritonavir should  
be used where possible in INI resistant  
patients.  
RTV ↔  
Protease Inhibitor:  
Fosamprenavir/ritonavir  
(FPV + RTV)  
Dolutegravir ↓  
AUC ↓ 35 %  
Cmax ↓ 24 %  
CƮ ↓ 49 %  
FPV ↔  
RTV ↔  
Protease Inhibitor:  
Nelfinavir  
Dolutegravir ↔  
This interaction has not been studied.  
Although an inhibitor of CYP3A4, based on  
data from other inhibitors, an increase is  
not expected. No dose adjustment is  
necessary.  
Protease Inhibitor:  
Loptinavir/ritonavir  
(LPV + RTV)  
Dolutegravir ↔  
Lopinavir/ritonavir did not change  
dolutegravir plasma concentration to a  
clinically relevant extent. No dose  
adjustment is necessary.  
AUC ↔  
Cmax  
↔
CƮ ↔  
LPV ↔  
RTV ↔  
Protease Inhibitor:  
Darunavir/ritonavir  
(DRV + RTV)  
Dolutegravir ↓  
AUC ↓ 32 %  
Cmax ↓ 11 %  
CƮ ↓ 38 %  
DRV ↔  
Darunavir/ritonavir did not change  
dolutegravir plasma concentration to a  
clinically relevant extent. No dose  
adjustment is necessary.  
RTV ↔  
Non-nucleoside Reverse Dolutegravir ↔  
Tenofovir did not change dolutegravir  
plasma concentration to a clinically  
relevant extent. No dose adjustment is  
necessary.  
Transcriptase Inhibitor:  
Tenofovir (TDV)  
TDV ↔  
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Protease Inhibitor:  
Loptinavir/ritonavir +  
Etravirine  
Dolutegravir ↔  
AUC ↑ 10 %  
Cmax ↑ 7 %  
CƮ ↑ 28 %  
LPV ↔  
Lopinavir/ritonavir and etravirine did not  
change dolutegravir plasma concentration  
to a clinically relevant extent. No dose  
adjustment is necessary.  
(LPV/RTV + ETR)  
RTV ↔  
ETR ↔  
Protease Inhibitor:  
Darunavir/ritonavir +  
Etravirine  
Dolutegravir ↓  
AUC ↓ 25 %  
Cmax ↓ 12 %  
CƮ ↓ 36 %  
DRV ↔  
Darunavir/ritonavir and etravirine did not  
change dolutegravir plasma concentration  
to a clinically relevant extent. No dose  
adjustment is necessary.  
(DRV/RTV + ETR)  
RTV ↔  
ETR ↔  
Other Medicines  
Dofetilide  
Dofetilide ↑  
Co-administration of dolutegravir has the  
potential to increase dofetilide or  
Pilsicainide  
Pilsicainide ↑  
pilsicainide plasma concentration via  
inhibition of OCT2 transporter; co-  
administration has not been studied.  
Dofetilide or pilsicainide co-administration  
with LUVIGEN is contraindicated due to  
the potential life-threatening toxicity  
caused by high dofetilide or pilsicainide  
concentration (see section 4.3).  
Oxcarbazepine  
Phenytoin  
Dolutegravir ↓  
Co-administration may decrease  
dolutegravir plasma concentration and has  
been studied. Co-administration with these  
metabolic inducers should be avoided.  
Phenobarbitone  
Carbamazepine  
St. John’s wort  
Antacids containing  
polyvalent cations (e.g.,  
Mg, Al or Ca)  
Dolutegravir ↓  
AUC ↓ 74 %  
Cmax ↓ 72 %  
C24 ↓ 74 %  
Co-administration of antacids containing  
polyvalent cations decreased dolutegravir  
plasma concentration.  
LUVIGEN is recommended to be  
administered 2 hours before or 6 hours  
after taking antacid products containing  
polyvalent cations.  
Calcium supplements  
Iron supplements  
Dolutegravir ↓  
AUC ↓ 39 %  
Cmax ↓ 37 %  
C24 ↓ 39 %  
LUVIGEN is recommended to be  
administered 2 hours before or 6 hours  
after taking products containing calcium, or  
alternatively, administer with food.  
LUVIGEN is recommended to be  
administered 2 hours before or 6 hours  
after taking products containing iron, or  
alternatively, administer with food.  
Dolutegravir ↓  
AUC ↓ 54 %  
Cmax ↓ 57 %  
C24 ↓ 56 %  
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Metformin  
Rifampicin  
Metformin ↑  
Co-administration of dolutegravir increased  
metformin plasma concentration.  
Metformin is contraindicated in patients  
taking LUVIGEN (see section 4.3).  
Rifampicin decreased dolutegravir plasma  
concentration. The recommended dose of  
LUVIGEN is 50 mg twice daily when co-  
administered with rifampicin. Alternatives  
to rifampicin should be used where  
possible for INI resistant patients.  
Dolutegravir ↓  
AUC ↓ 54 %  
Cmax ↓ 43 %  
CƮ ↓ 72 %  
Oral contraceptives  
(Ethinyl oestradiol (EE)  
and Norgestromin  
(NGMN))  
Effect of dolutegravir:  
EE ↔  
Dolutegravir did not change ethinyl  
oestradiol and norgestromin plasma  
concentrations to a clinically relevant  
extent. No dose adjustment of oral  
contraceptives is necessary when co-  
administered with LUVIGEN.  
AUC ↑ 3 %  
Cmax ↓ 1 %  
CƮ ↑ 2 %  
Effect of dolutegravir:  
NGMN ↔  
AUC ↓ 2 %  
Cmax ↓ 11 %  
CƮ ↓ 7 %  
Methadone  
Effect of dolutegravir:  
Methadone ↔  
AUC ↓ 2 %  
Dolutegravir did not change methadone  
plasma concentrations to a clinically  
relevant extent. No dose adjustment of  
methadone is necessary when co-  
administered with LUVIGEN.  
Cmax ↔ 0 %  
CƮ ↓ 1 %  
Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no significant change; AUC = area under the  
concentration versus time curve; Cmax = maximum observed concentration; Cτ = concentration  
at the end of dosing interval.  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
LUVIGEN is contraindicated in pregnancy and lactation. Neural tube defects have been noted  
in an observational study in humans, where dolutegravir-based regimens were used at the time  
of conception and early pregnancy, (see section 4.3).  
Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity  
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studies in animals. Late onset neurological disorders, including seizures, have been observed  
in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine  
in utero, (see Mitochondrial Dysfunction under section 4.4).  
LUVIGEN should not be prescribed in women who plan to become pregnant. Women of child-  
bearing age should not use LUVIGEN unless they are reliably using highly effective  
contraception. Treatment with LUVIGEN should not be initiated without a medically supervised  
negative pregnancy test. This test should be repeated at frequent intervals during treatment  
with LUVIGEN; and especially in the event that pregnancy is suspected.  
Breastfeeding  
Mothers breastfeeding their infants should not use LUVIGEN. Lamivudine is excreted in human  
milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk and it  
is not unknown whether dolutegravir is excreted in human milk.  
4.7 Effects on ability to drive and use machines  
LUVIGEN may affect the ability to drive and use machines.  
Patients should ensure that they do not engage in driving or using machines until they know  
how LUVIGEN affects them.  
4.8 Undesirable effects  
Tabulated summary of adverse reactions  
LUVIGEN can have side effects  
Lamivudine  
The following side effects have been reported during therapy for HIV disease with LUVIGEN  
tablets alone and in combination with other antiretrovirals.  
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Blood and lymphatic system disorders  
Less frequent: neutropenia, anaemia, thrombocytopenia  
Frequency unknown: pure red cell aplasia  
Metabolism and nutrition disorders  
Frequent: hyperlactataemia  
Less frequent: lactic acidosis (see section 4.4), lipodystrophy (redistribution/accumulation of  
body fat (see section 4.4)  
Nervous system disorders  
Frequent: headache  
Less frequent: peripheral neuropathy (or paraesthesia), late onset neurological disorders in  
children exposed in utero  
Gastrointestinal disorders  
Frequent: nausea, vomiting, upper abdominal pain, diarrhoea  
Less frequent: pancreatitis, elevations in serum amylase  
Hepato-biliary disorders  
Less frequent: transient rises in liver enzymes (AST, ALT)  
Skin and subcutaneous tissue disorders  
Frequent: rash, alopecia  
Musculoskeletal and connective tissue disorders  
Frequent: arthralgia, muscle disorders  
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Less frequent: rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures  
General disorders and administrative site conditions  
Frequent: fatigue, fever, malaise  
Tenofovir disoproxil fumarate  
Immune system disorders  
Less frequent: allergic reaction  
Metabolism and nutrition disorders  
Less frequent: hypophosphataemia, lactic acidosis  
Respiratory, thoracic and mediastinal disorders  
Frequent: dyspnoea  
Gastrointestinal disorders  
Frequent: abdominal pain, anorexia, dyspepsia, flatulence  
Less frequent: increased amylase, pancreatitis  
Hepato-biliary disorders  
Less frequent: increased liver enzymes, hepatitis  
Renal and urinary disorders  
Frequent: renal insufficiency, renal failure, acute renal failure, proximal tubulopathy,  
proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus  
Dolutegravir  
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Immune system disorders  
Less frequent: hypersensitivity, immune reconstitution inflammatory syndrome (see section  
4.4)  
Psychiatric disorders  
Frequent: insomnia  
Nervous system disorders  
Frequent: headache, dizziness, abnormal dreams  
Gastrointestinal disorders  
Frequent: nausea, diarrhoea  
Less frequent: vomiting, flatulence, upper abdominal pain  
Frequency unknown: abdominal pain, abdominal discomfort  
Hepato-biliary disorders  
Frequency unknown: hepatitis  
Skin and subcutaneous tissue disorders  
Frequent: rash, pruritus  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It  
allows continued monitoring of the benefit/risk balance of the medicine. Health care providers  
are asked to report any suspected adverse reactions via the “6.04 Adverse Drug Reactions  
Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za or to  
the Holder of certificate of registration through the mail: pvg.cdma@heterogroups.com.  
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4.9 Overdose  
Tenofovir disoproxil fumarate:  
If overdose occurs the patient must be monitored for evidence of toxicity and palliative  
supportive treatment be applied as necessary.  
Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir  
is 134 ml/min. The elimination of tenofovir by peritoneal dialysis has not been studied.  
Lamivudine:  
Limited data are available on the consequences of ingestion of acute overdoses in humans.  
If overdosage occurs the patient should be monitored, and palliative supportive treatment  
applied as required.  
Dolutegravir:  
Management should be as clinically indicated or as recommended by the national poisons  
centre, where available. There is no specific treatment for an overdose of LUVIGEN. If  
overdose occurs, the patient should be treated supportively with appropriate monitoring as  
necessary. As LUVIGEN is highly bound to plasma proteins, it is unlikely that it will be  
significantly removed by dialysis.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacological classification: A 20.2.8 Antimicrobial (Chemotherapeutic) Medicines.  
Antiviral Medicines.  
Lamivudine  
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Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV-1  
and HIV-2 replication in vitro.  
Lamivudine is metabolised intracellularly to the 5'-triphosphate which has an intracellular half-  
life of 16 - 19 hours. Lamivudine 5'-triphosphate is a weak inhibitor of the RNA and DNA  
dependent activities of HIV reverse transcriptase; its mode of action is a chain terminator of HIV  
reverse transcription.  
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who  
have received lamivudine therapy.  
Lamivudine-resistant HIV-1 mutants are cross-resistant to didanosine and zalcitabine. In some  
patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple  
reverse transcriptase inhibitors, including lamivudine, have emerged.  
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on  
mammalian cell and mitochondrial DNA content.  
Tenofovir  
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analogue of  
adenosine monophosphate and is converted in vivo to tenofovir. It is a nucleoside reverse  
transcriptase inhibitor.  
Tenofovir is phosphorylated by cellular enzymes to form tenofovir diphosphate.  
Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase, by competing with the  
natural substrate deoxyadenosine 5'-triphosphate and, after incorporation in DNA, by chain  
termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β  
and mitochondrial DNA polymerase γ.  
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Drug Resistance:  
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro and a K65R  
mutation in reverse transcriptase have been selected in vitro and in some patients treated with  
tenofovir in combination with certain antiretroviral medicines. In treatment naive patients treated  
with tenofovir + lamivudine + efavirenz, viral isolates from 17 % patients with virologic failure  
showed reduced susceptibility to tenofovir.  
In treatment-experienced patients, some of the tenofovir-treated patients with virologic failure  
through week 96 showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant  
isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R  
amino acid substitution.  
Cross-resistance:  
Cross-resistance among certain reverse transcriptase inhibitors has been recognised. The  
K65R mutation can also be selected by abacavir, didanosine or zalcitabine and results in  
reduced susceptibility to these medicines plus lamivudine, emtricitabine and tenofovir.  
Tenofovir disoproxil fumarate should be avoided in antiretroviral experienced patients with  
strains harbouring the K65R mutation. Patients with HIV-1 expressing three or more thymidine  
analogue associated mutations (TAMs) that included either the M41L or L210W reverse  
transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate.  
Antiviral activity:  
The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 has  
been assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral  
blood lymphocytes. The IC50 (50 % inhibitory concentration) values for tenofovir were in the  
range of 0,04 μM to 8,5 μM. In medicine combination studies of tenofovir with nucleoside  
reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine,  
zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine),  
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and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to  
synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV-1  
clades A, B, C, D, E, F, G, and O (IC50 values ranged from 0,5 μM to 2,2 μM). The IC50 values  
of tenofovir against HIV-2 ranged from 1,6 μM to 4,9 μM.  
Special Populations:  
Paediatrics and the elderly:  
Pharmacokinetic studies have not been performed in children (< 18 years) or in the elderly (>  
65 years).  
Hepatic impairment:  
Tenofovir pharmacokinetics after a 300 mg single dose have been studied in non-HIV infected  
patients with moderate to severe hepatic impairment. There were no substantial alterations in  
tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired  
patients. Change in tenofovir dosing is not required in patients with hepatic impairment.  
Renal impairment:  
Tenofovir pharmacokinetics are altered in patients with renal impairment. In patients with  
creatinine clearance < 50 ml/min or with end-stage renal disease (ESRD) requiring dialysis,  
Cmax, and AUCo-∞ of tenofovir were increased. It is recommended that the dosing interval for  
tenofovir be modified in patients with creatinine clearance < 50 ml/min or in patients with ESRD  
who require dialysis (see section 4.2). Tenofovir is efficiently removed by haemodialysis with  
an extraction coefficient of approximately 54 %. Following a single 300 mg dose of tenofovir, a  
four-hour haemodialysis session removed approximately 10 % of the administered tenofovir  
dose.  
Dolutegravir  
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Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the  
strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for  
the HIV replication cycle. In vitro, dolutegravir dissociates slowly from the active site of the wild-  
type integrase-DNA complex (t1/2 71 hours).  
Resistance in vitro:  
Isolation from wild-type HIV-1: Viruses highly resistant to dolutegravir have not been observed  
during HIV-1 passage. During wild-type HIV-1 passage in the presence of dolutegravir  
integrase substitutions observed were S153Y and S153F with FCs ≤ 4,1 for strain IIIB, or E92Q  
with FC = 3,1 and G193E with FC = 3,2 for strain NL432.  
Additional passage of wild-type subtype B, C, and A/G viruses in the presence of dolutegravir  
selected for R263K, G118R and S153T.  
Anti-HIV activity Against Resistant Strains: Reverse Transcriptase Inhibitor-and Protease  
Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent potency against 2 non-  
nucleoside (NN)-RTl-resistant, 3 nucleoside (N)-RTl-resistant and 2 Pl-resistant HIV-1 mutant  
clones (1 triple and 1 sextuple) compared to the wild-type strain.  
lntegrase Inhibitor-Resistant HIV-1 Strains: Dolutegravir showed anti-HIV activity (susceptibility)  
with FC < 5 against 27 of 28 integrase inhibitor -resistant mutant viruses with single  
substitutions including T66A/l/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H.  
lntegrase Inhibitor-Resistant HIV-2 Strains: Site directed mutant HIV-2 viruses were  
constructed based on subjects infected with HIV-2 and treated with raltegravir who showed  
virologic failure. Overall the HIV-2 FCs observed were similar to HIV-1 FCs observed for similar  
pathway mutations.  
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Resistance in vivo: integrase inhibitor naive patients: No integrase inhibitor (INI) resistant  
mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with  
dolutegravir 50 mg once daily in treatment - naive studies.  
Effects on Renal Function: The effect of dolutegravir on serum creatinine clearance (CrCI),  
glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow  
(ERPF) using para-aminohippurate (PAH) as the probe was evaluated. A small decrease of 10-  
14 % in mean serum creatinine clearance (CrCI) was observed with dolutegravir within the first  
week of treatment. Dolutegravir had no significant effect on glomerular filtration rate (GFR) or  
the effective renal plasma flow (ERPF). In vitro studies suggest that the increases in creatinine  
observed in clinical studies are due to the non-pathologic inhibition of the organic cation  
transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of  
creatinine.  
Special Populations:  
Adolescents:  
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected  
adolescents (12 to < 18 years of age) showed that dolutegravir 50 mg once daily dosage  
resulted in dolutegravir exposure comparable to that observed in adults who received  
dolutegravir 50 mg once daily.  
Table 1: Adolescent pharmacokinetic parameters  
Age/weight  
Dolutegravir  
Dose  
Dolutegravir Pharmacokinetic Parameter  
Estimates  
Geometric Mean (CV %)  
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AUC(0-24)  
Cmax  
C24  
μg.hr/ml  
μg/ml  
μg/ml  
12 to < 18 years  
50 mg once  
46 (43)  
3,49 (38)  
0,90 (59)  
a
a
≥ 40 kg  
daily  
a
one subject weighing 37 kg received 35 mg once daily.  
Elderly:  
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed  
that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic  
data for dolutegravir in subjects of > 65 years old are limited.  
Renal impairment:  
Renal clearance of unchanged medicine is a minor pathway of elimination for dolutegravir. A  
study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal  
impairment (CLcr < 30 ml/min). No clinically important pharmacokinetic differences between  
subjects with severe renal impairment (Clcr < 30 ml/min) and matching healthy subjects were  
observed, AUC, Cmax, and C24 of dolutegravir were decreased by 40 %, 23 % and 43 %,  
respectively, compared with those in matched healthy subjects. No dosage adjustment is  
necessary for patients with renal impairment. Dolutegravir has not been studied in patients on  
dialysis, though differences in exposure are not expected.  
Hepatic impairment:  
Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8  
subjects with moderate hepatic impairment (Child-Pugh category B score 7 to 9) to 8 matched  
healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the  
two groups. No dosage adjustment is necessary for patients with mild hepatic impairment. The  
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effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been  
studied.  
Polymorphisms in Metabolising Enzymes:  
There is no evidence that common polymorphisms in metabolising enzymes alter dolutegravir  
pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics  
samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n = 7)  
genotypes conferring poor dolutegravir metabolism had a 32 % lower clearance of dolutegravir  
and 46 % higher AUC compared with subjects with genotypes associated with normal  
metabolism via UGT1A1(n = 41). Polymorphisms in CYP3A4, CYP3A5, and NR1I2 were not  
associated with differences in the pharmacokinetics of dolutegravir.  
Co-infection with Hepatitis B or C:  
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no  
clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with  
hepatitis B co-infection.  
5.2 Pharmacokinetic properties  
Dolutegravir, Lamivudine and Tenofovir disoproxil fumarate Tablets 50 mg / 300 mg /  
300 mg pharmacokinetic data  
a
a
a
Dolutegravir  
Lamivudine  
Tenofovir  
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Arithmetic mean  
(% CV)  
Arithmetic mean  
Arithmetic mean  
(% CV)  
Parameter  
(% CV)  
AUC0-t (ng.hr/ml)  
49314,31 (42,04)  
11840,36 (23,35)  
3203,17 (24,33)  
AUC0-inf (ng.hr/ml)  
Cmax (ng/ml)  
52859,55 (43,30)  
2121,86 (36,74)  
12124,10 (22,45)  
2055,08 (27,21)  
3442,56 (24,01)  
470,15 (35,88)  
a based on the Single oral Dose Crossover Bioequivalence Study  
Following oral single dose administration of dolutegravir, lamivudine and tenofovir disoproxil  
fumarate (50 mg / 300 mg / 300 mg) have been evaluated in healthy adult subjects with 56  
volunteers. Estimated the pharmacokinetic parameters after single oral dose of fixed dose  
single tablet 2121,86 ng/ml, 2055,08 ng/ml and 470,15 ng/ml for Cmax, 49314,31 ng.hr/ml,  
11840,36 ng.hr/ml and 3203,17 ng.hr/ml for AUC0-t, 52859,55 ng.hr/ml, 12124,10 ng.hr/ml,  
3442,56 ng.hr/ml for AUC0-inf for dolutegravir, lamivudine and tenofovir respectively.  
Peak plasma concentrations (Tmax) were achieved and reported median (min-max), 2,75 (0,52 –  
10,02) hr, 2,00 (0,75 – 4,67) hr and 0,76 (0,50 – 4,00) hr for dolutegravir, lamivudine and  
tenofovir respectively.  
Calculated the terminal half-life (T1/2 (hr)) for dolutegravir, lamivudine and tenofovir  
approximately was 16,54 hr, 6,38 hr and 18,83 hr respectively.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
Croscarmellose sodium  
Hydroxypropyl cellulose  
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•
•
•
•
Magnesium stearate  
Mannitol  
Microcrystalline cellulose  
Opadry II Orange (containing titanium dioxide (colourant), talc, povidone, red iron oxide  
(colourant), yellow iron oxide (colourant) and polyethylene glycol/macrogol)  
Sodium starch glycolate and  
•
•
Sodium stearyl fumarate.  
6.2 Incompatibilities  
Not applicable  
6.3 Shelf life  
36 months  
6.4 Special precautions for storage  
•
•
•
•
•
Store at or below 30 °C.  
Keep the container tightly closed.  
Keep the tablets in the original container until required for use.  
Protect from light and moisture.  
This medicine does not require any special storage conditions.  
6.5 Nature and contents of container  
28’s and 30’s Count HDPE container: White opaque heavy weight high density polyethylene  
container 100 cc with 38 mm neck, with a dessicant canister 2,0 g silica gel, a cotton filler 9  
gram/yard and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-  
resistant cap (CR) with opening illustration embossed on top with a 38 mm pulp liner.  
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28’s and 30’s Count HDPE container: White opaque heavy weight density polyethylene  
container 100 cc with 38 mm neck, with a desiccant canister 2.0 g silica gel, enclosed with  
white opaque polypropylene, continues thread (CT) closer with wad having induction sealing  
liner.  
56’s and 60’s Count HDPE container: White opaque heavy weight high density polyethylene  
container 150 cc with 38 mm neck, with a dessicant canister 2,0 g silica gel, a cotton filler 9  
gram/yard and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-  
resistant cap (CR) with opening illustration embossed on top with a 38 mm pulp liner.  
84’s Count HDPE container: White opaque heavy weight high density polyethylene container  
200 cc with 38 mm neck, with a dessicant canister 2,0 g silica gel, a cotton filler 9 gram/yard  
and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-resistant cap  
(CR) with opening illustration embossed on top with a 38 mm pulp liner.  
90’s Count HDPE container: White opaque heavy weight high density polyethylene container  
200 cc with 38 mm neck, with a dessicant canister 2,0 g silica gel, a cotton filler 9 gram/yard  
and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-resistant cap  
(CR) with opening illustration embossed on top with a 38 mm pulp liner.  
84’s and 90’s Count HDPE container: White opaque heavy weight density polyethylene  
container 200 cc with 38 mm neck, with a desiccant canister 4.0 g silica gel, enclosed with  
white opaque polypropylene, continues thread (CT) closer with wad having induction sealing  
liner.  
100’s Count HDPE container: White opaque heavy weight high density polyethylene  
container 250 cc with 53 mm neck, with a dessicant canister 3,0 g silica gel, a cotton filler 9  
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gram/yard and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-  
resistant cap (CR) with opening illustration embossed on top with a 53 mm pulp liner.  
Simulated Bulk Pack:  
100's count Triple Laminated LDPE bag:  
Plain triple laminated bag (28"x45") (12 Microns PET/ 12 Microns aluminium foil/110 Microns  
white opaque LDPE).  
750’s Count HDPE container: White opaque heavy weight high density polyethylene  
container 1500 cc with 53 mm neck, with a dessicant canister 3,0 g silica gel, a cotton filler 9  
gram/yard and a heat seal liner, enclosed with a white opaque, polypropylene, ribbed, child-  
resistant cap (CR) with opening illustration embossed on top with a 53 mm pulp liner.  
Available in pack sizes of 28, 30, 56, 60, 84, 90, 100 or 750 tablets.  
Not all pack sizes may be marketed.  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd.  
Waterfall Corporate Campus  
Building No. 2, First floor  
74 Waterfall Drive  
Midrand  
2066  
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8 REGISTRATION NUMBER  
52/20.2.8/0948.946  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
10 October 2018  
DATE OF REVISION OF THE TEXT  
06 March 2024.  
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