Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
PROFESSIONAL INFORMATION FOR HETVIR 50  
SCHEDULING STATUS S4  
1
2
NAME OF THE MEDICINE  
HETVIR 50 (film coated tablet)  
QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film coated tablet contains dolutegravir sodium equivalent to 50 mg  
dolutegravir.  
Contains sugar (140,4 mg mannitol).  
3
4
PHARMACEUTICAL FORM  
Pink, round, biconvex, film coated tablets debossed with 'H' on one side and 'D 13'  
on the other side.  
CLINICAL PARTICULARS  
4.1  
Therapeutic indications  
HETVIR 50 is indicated for the treatment of human immunodeficiency virus (HIV)  
infection in combination with other antiretroviral medicines in adults aged 18 years  
and older.  
4.2  
Posology and method of administration  
Posology:  
HETVIR 50 therapy should be initiated by a medical practitioner experienced in the  
management of HIV infection. HETVIR 50 can be taken with or without food.  
JAN 2023  
Initials………….  
Page 1 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
Special populations:  
Elderly:  
There are limited data available on the use of HETVIR 50 in patients aged 65 years  
and over. However, there is no evidence that elderly patients require a different  
dose than younger adult patients (see Section 5.2).  
Renal impairment:  
No dosage adjustment is required in patients with mild, moderate or severe (CrCℓ  
< 30 ml/min, not on dialysis) renal impairment. No data are available in subjects  
receiving dialysis, although differences in pharmacokinetics are not expected in this  
population (see Section 5.2).  
Treatment with HETVIR 50 resulted in an early small increase of mean serum  
creatinine levels by 10 – 14 % which remained stable over time and is not  
considered clinically relevant (see Section 4.8).  
Hepatic impairment:  
10BNo dosage adjustment is required in patients with mild hepatic impairment  
(Child-Pugh grade A or B). HETVIR 50 is contraindicated in patients with moderate  
or severe hepatic impairment (see Section 4.3).  
Paediatric population:  
No information.  
Method of administration:  
Adults:  
Treatment-naive:  
JAN 2023  
Initials………….  
Page 2 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
For patients initiating antiretroviral therapy for the first time (treatment-naive) the  
recommended dose of HETVIR 50 is 50 mg once daily.  
Treatment-experienced, and integrase inhibitor naive:  
For patients who are treatment experienced and have not previously been treated  
with an integrase inhibitor, the recommended dose of HETVIR 50 is 50 mg once  
daily.  
Integrase inhibitor resistant:  
For patients with integrase inhibitor resistance, the recommended dose of HETVIR  
50 is 50 mg twice daily.  
4.3  
Contraindications  
•
Hypersensitivity to dolutegravir or any of the ingredients of HETVIR 50,  
including the excipients.  
•
•
•
HETVIR 50 is contraindicated in combination with dofetilide and pilsicainide.  
HETVIR 50 is contraindicated in moderate and severe hepatic impairment.  
Metformin is contraindicated in patients taking HETVIR 50.  
4.4  
Special warnings and precautions for use  
Hypersensitivity Reactions:  
Hypersensitivity reactions have been reported with integrase inhibitors, including  
HETVIR 50 and were characterised by rash, constitutional findings and sometimes,  
organ dysfunction, including liver injury. Discontinue HETVIR 50 and other  
suspected medicines 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 and appropriate therapy initiated. Delay in  
JAN 2023  
Initials………….  
Page 3 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
stopping treatment with HETVIR 50 or other suspect medicines after the onset of  
hypersensitivity may result in a life-threatening reaction.  
Lipodystrophy and Metabolic Abnormalities:  
Combination antiretroviral therapy has been associated with the  
redistribution/accumulation of body fat, including central obesity, dorso-cervical fat  
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement  
and elevated serum lipid and glucose levels in HIV patients. Clinical examination  
should include evaluation for physical signs of fat redistribution. Patients with  
evidence of lipodystrophy should have a thorough cardiovascular risk assessment.  
Immune Reconstitution Syndrome:  
In HIV-infected patients with severe immune deficiency at the time of initiation of  
antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual  
opportunistic infections may arise and cause serious clinical conditions, or  
aggravation of symptoms. Typically, such reactions have been observed within the  
first few weeks or months of initiation of ART. Relevant examples are tuberculosis,  
cytomegalovirus retinitis, generalised and/or focal atypical mycobacterial infections  
and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must  
be evaluated without delay and treatment initiated when necessary. Auto-immune  
disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome)  
have also been reported to occur in the setting of immune reconstitution, however,  
the time to onset is more variable and can occur many months after initiation of  
treatment and sometimes can be an atypical presentation.  
Liver chemistry elevations consistent with immune reconstitution syndrome were  
observed in some hepatitis B and/or C co-infected patients at the start of HETVIR  
JAN 2023  
Initials………….  
Page 4 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
50 therapy. Monitoring of liver chemistries is recommended in patients with hepatitis  
B and/or C co-infection. Particular diligence should be applied in initiating or  
maintaining effective hepatitis B therapy (referring to treatment guidelines) when  
starting dolutegravir-based therapy in hepatitis B co-infected patients (see Section  
4.8).  
Osteonecrosis:  
Although the aetiology is considered to be multifactorial (including corticosteroid  
use, alcohol consumption, severe immunosuppression, higher body mass index),  
cases of osteonecrosis have been reported, particularly in patients with advanced  
HIV-disease and/or long-term exposure to combination antiretroviral therapy  
(cART). Patients should be advised to seek medical advice if they experience joint  
aches and pain, joint stiffness or difficulty in movement.  
Hepatic Impairment:  
The unbound fraction of dolutegravir in the blood is doubled in patients with  
moderate hepatic impairment.  
HETVIR 50 is contraindicated in patients with moderate or severe hepatic  
impairment (see Section 4.3).  
Interactions:  
Caution should be given to co-administering medicines (prescription and non-  
prescription) that may change the exposure of HETVIR 50 or medicines that may  
have their exposure changed by HETVIR 50 (see Section 4.3 and Section 4.5).  
The co-administration of HETVIR 50 with etravirine (ETR) is not recommended  
unless the patient is also receiving concomitant atazanavir and ritonavir (ATV and  
JAN 2023  
Initials………….  
Page 5 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
RTV), lopinavir and ritonavir (LPV and RTV) or darunavir and ritonavir (DRV and  
RTV) (see Section 4.5).  
The recommended dose of HETVIR 50 is 50 mg twice daily when co-administered  
with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see Section 4.5).  
HETVIR 50 should not be co-administered with polyvalent cation-containing  
antacids. HETVIR 50 is recommended to be administered 2 hours before or 6 hours  
after these medicines (see Section 4.5).  
Metformin concentrations may be increased by HETVIR 50. Metformin is  
contraindicated in patients taking HETVIR 50 (see Section 4.3).  
Co-infection with Hepatitis B or C:  
In Phase Ill studies, patients with hepatitis B and/or C co-infection were permitted to  
enrol provided that baseline liver chemistry tests did not exceed 5 times the upper  
limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis  
B and/or C was similar to that observed in patients without hepatitis B or C co-  
infection, although the rates of AST and ALT abnormalities were higher in the  
subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver  
chemistry elevations consistent with immune reconstitution syndrome were  
observed in some subjects with hepatitis B and/or C co-infection at the start of  
HETVIR 50 therapy, particularly in those whose anti-hepatitis B therapy was  
withdrawn.  
Opportunistic Infections:  
Patients receiving HETVIR 50 or any other antiretroviral therapy may still develop  
opportunistic infections and other complications of HIV infection. Therefore, patients  
JAN 2023  
Initials………….  
Page 6 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
should remain under close clinical observation by medical practitioners experienced  
in the treatment of these associated HIV diseases.  
Transmission of Infection:  
Patients should be advised that current antiretroviral therapy, including HETVIR 50,  
has not been proven to prevent the risk of transmission of HIV to others through  
sexual contact or blood contamination. Appropriate precautions should continue to  
be taken.  
HETVIR 50 contains mannitol and may have a laxative effect.  
Paediatric population  
No information available.  
4.5  
Interaction with other medicines and other forms of interaction  
Effect of HETVIR 50 on the Pharmacokinetics of Other Medicines:  
In vitro, HETVIR 50 demonstrated no direct, or weak inhibition (IC50 > 50 µM) of  
the enzymes cytochrome P450 (CYP)1A2, 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, HETVIR 50 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  
JAN 2023  
Initials………….  
Page 7 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
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).  
In medicine interaction studies, HETVIR 50 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 oestradiol.  
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2). Based  
on this observation, HETVIR 50 may increase plasma concentrations of medicines  
in which excretion is dependent upon OCT2 (dofetilide, pilsicainide and metformin)  
Therefore these medicines (OCT2 inhibitors) are contraindicated for use with  
HETVIR 50 (see Section 4.3 and Table 2: MEDICINE INTERACTIONS - Other  
Medicines).  
Effect of Other Medicines on the Pharmacokinetics of HETVIR 50:  
HETVIR 50 is eliminated mainly through metabolism by UGT1A1. HETVIR 50 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 HETVIR 50.  
Co-administration of HETVIR 50 and other medicines that inhibit UGT1A1,  
UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma  
concentration (see Table 2).  
Efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir each  
reduced the plasma concentrations of dolutegravir significantly and require HETVIR  
50 dose adjustment to 50 mg twice daily. Etravirine also reduced plasma  
concentrations, but the effect of etravirine was mitigated by co-administration of the  
JAN 2023  
Initials………….  
Page 8 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to be  
mitigated by atazanavir/ritonavir. Therefore, no HETVIR 50 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 HETVIR 50. Caution is warranted and  
clinical monitoring is recommended when these combinations are given in INI-  
resistant patients (see Table 2: MEDICINE INTERACTIONS - HIV-1 Antiviral  
Medicines). An 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 HETVIR 50 dose adjustment  
is required when co-administered with these medicines.  
Table 2: Medicine Interactions  
Concomitant  
Effect on Concentration of HETVIR  
Medicine Class:  
Medicine Name  
Clinical Comment  
50 or Concomitant Medicine  
HIV-1 Antiviral Medicines  
Etravirine decreased dolutegravir  
plasma concentration, which may  
result in loss of virologic response  
and possible resistance to  
dolutegravir. HETVIR 50 should  
not be used with etravirine without  
co-administration of  
Dolutegravir ↓  
AUC ↓ 71 %  
Non-nucleoside  
Reverse Transcriptase  
Inhibitor:  
Cmax  
R
R
↓ 52 %  
CƮ ↓ 88 %  
R
R
Etravirine (ETR)  
ETR ↔  
atazanavir/ritonavir,  
darunavir/ritonavir or  
lopinavir/ritonavir.  
Efavirenz decreased dolutegravir  
plasma concentrations.  
Dolutegravir ↓  
AUC ↓ 57 %  
Non-nucleoside  
Reverse Transcriptase  
Inhibitor:  
The recommended dose of  
HETVIR 50 is 50 mg twice daily  
when co-administered with  
efavirenz. Alternative  
Cmax  
CƮ ↓ 75 %  
EFV ↔  
R
R
↓ 39 %  
R
R
Efavirenz (EFV)  
JAN 2023  
Initials………….  
Page 9 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
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  
Non-nucleoside  
exposure is likely similar to or less  
Reverse Transcriptase  
Inhibitor:  
Dolutegravir ↓  
than that of efavirenz. The  
recommended dose of HETVIR  
50 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.  
Nevirapine  
Dolutegravir ↑  
AUC ↑ 91 %  
Atazanavir increased dolutegravir  
plasma concentration. No dose  
adjustment is necessary.  
Protease Inhibitor:  
Atazanavir (ATV)  
Cmax  
R
R
↑ 49 %  
CƮ ↑ 180 %  
R
R
ATV ↔  
Dolutegravir ↑  
AUC ↑ 62 %  
Atazanavir/ritonavir increased  
dolutegravir plasma  
Protease Inhibitor:  
Atazanavir/ritonavir  
(ATV + RTV)  
Cmax  
R
R
↑ 33 %  
CƮ ↑ 121 %  
R
R
concentration. No dose  
adjustment is necessary.  
ATV ↔  
RTV ↔  
Tipranavir/ritonavir decreases  
dolutegravir concentrations. The  
recommended dose of HETVIR  
50 is 50 mg twice daily when co-  
administered with  
Dolutegravir ↓  
AUC ↓ 59 %  
Protease Inhibitor:  
Tipranavir/ritonavir  
(TPV + RTV)  
Cmax  
R
R
↓ 47 %  
CƮ ↓ 76 %  
R
R
tipranavir/ritonavir. Alternative  
combinations that do not include  
tipranavir/ritonavir should be used  
where possible in INI resistant  
patients.  
TPV ↔  
RTV ↔  
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  
Dolutegravir ↓  
AUC ↓ 35 %  
Protease Inhibitor:  
Fosamprenavir/ritonavir  
(FPV + RTV)  
Cmax  
R
R
↓ 24 %  
CƮ ↓ 49 %  
R
R
FPV ↔  
RTV ↔  
fosamprenavir/ritonavir should be  
used where possible in INI  
resistant patients.  
JAN 2023  
Initials………….  
Page 10 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
This interaction has not been  
studied. Although an inhibitor of  
Protease Inhibitor:  
Nelfinavir  
Dolutegravir ↔  
CYP3A4, based on data from  
other inhibitors, an increase is not  
expected. No dose adjustment is  
necessary.  
Dolutegravir ↔  
AUC ↔  
Lopinavir/ritonavir did not change  
dolutegravir plasma concentration  
to a clinically relevant extent. No  
dose adjustment is necessary.  
Protease Inhibitor:  
Loptinavir/ritonavir  
(LPV + RTV)  
Cmax  
R
R
↔
CƮ  
R
R
↔
LPV ↔  
RTV ↔  
Dolutegravir ↓  
AUC ↓ 32 %  
Darunavir/ritonavir did not change  
dolutegravir plasma concentration  
to a clinically relevant extent. No  
dose adjustment is necessary.  
Protease Inhibitor:  
Darunavir/ritonavir  
(DRV + RTV)  
Cmax  
R
R
↓ 11 %  
CƮ ↓ 38 %  
R
R
DRV ↔  
RTV ↔  
Non-nucleoside  
Reverse Transcriptase  
Inhibitor:  
Tenofovir did not change  
dolutegravir plasma concentration  
to a clinically relevant extent. No  
dose adjustment is necessary.  
Dolutegravir ↔TDV ↔  
Tenofovir (TDV)  
Dolutegravir ↔  
AUC ↑ 10 %  
Lopinavir/ritonavir and etravirine  
did not change dolutegravir  
plasma concentration to a  
Protease Inhibitor:  
Loptinavir/ritonavir +  
Etravirine  
Cmax  
R
R
↑ 7 %  
CƮ ↑ 28 %  
R
R
LPV ↔  
clinically relevant extent. No dose  
adjustment is necessary.  
(LPV/RTV + ETR)  
RTV ↔  
ETR ↔  
Dolutegravir ↓  
AUC ↓ 25 %  
Darunavir/ritonavir and etravirine  
did not change dolutegravir  
plasma concentration to a  
Protease Inhibitor:  
Darunavir/ritonavir +  
Etravirine  
Cmax  
R
R
↓ 12 %  
CƮ ↓ 36 %  
R
R
DRV ↔  
RTV ↔  
ETR ↔  
clinically relevant extent. No dose  
adjustment is necessary.  
(DRV/RTV + ETR)  
Other Medicines  
Co-administration of dolutegravir  
has the potential to increase  
dofetilide or pilsicainide plasma  
concentration via inhibition of  
OCT2 transporter; co-  
Antidysrythmics  
Dofetilide  
Dofetilide ↑  
administration has not been  
studied. Dofetilide or pilsicainide  
co-administration with HETVIR 50  
is contraindicated due to the  
potential life-threatening toxicity  
caused by high dofetilide or  
pilsicainide concentration (see  
Section 4.3).  
Pilsicainide ↑  
Pilsicainide  
Oxcarbazepine  
JAN 2023  
Dolutegravir ↓  
Co-administration may decrease  
Initials………….  
Page 11 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
Phenytoin  
dolutegravir plasma concentration  
and has been studied. Co-  
administration with these  
Phenobarbitone  
Carbamazepine  
St. John’s wort  
metabolic inducers should be  
avoided.  
Co-administration of antacids  
containing polyvalent cations  
decreased dolutegravir plasma  
concentration.  
Dolutegravir ↓  
AUC ↓ 74 %  
Antacids containing  
polyvalent cations (e.g., Cmax  
R
R
↓ 72 %  
HETVIR 50 is recommended to  
be administered 2 hours before or  
6 hours after taking antacid  
products containing polyvalent  
cations.  
Mg, Al or Ca)  
C24  
R
R
↓ 74 %  
HETVIR 50 is recommended to  
be administered 2 hours before or  
6 hours after taking products  
containing calcium, or  
Dolutegravir ↓  
AUC ↓ 39 %  
Calcium supplements  
Iron supplements  
Metformin  
Cmax  
R
R
↓ 37 %  
C24 ↓ 39 %  
R
R
alternatively, administer with food.  
HETVIR 50 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  
R
R
↓ 57 %  
C24 ↓ 56 %  
R
R
Co-administration of dolutegravir  
increased metformin plasma  
concentration. Metformin is  
contraindicated in patients taking  
HETVIR 500 (see Section 4.3).  
Rifampicin decreased dolutegravir  
plasma concentration. The  
recommended dose of HETVIR  
50 is 50 mg twice daily when co-  
administered with rifampicin.  
Alternatives to  
Metformin ↑  
Dolutegravir ↓  
AUC ↓ 54 %  
Rifampicin  
Cmax  
R
R
↓ 43 %  
CƮ ↓ 72 %  
R
R
rifampicin should be used where  
possible for INI resistant patients.  
Effect of dolutegravir:  
EE ↔  
Dolutegravir did not change  
ethinyl oestradiol and  
AUC ↑ 3 %  
Cmax  
R
R
↓ 1 %  
Oral contraceptives  
(Ethinyl oestradiol (EE)  
and Norgestromin  
(NGMN))  
norgestromin plasma  
CƮ ↑ 2 %  
R
R
concentrations to a clinically  
relevant extent. No dose  
adjustment of oral contraceptives  
is necessary when co-  
Effect of dolutegravir:  
NGMN ↔  
AUC ↓ 2 %  
administered with HETVIR 50.  
Cmax  
R
R
↓ 11 %  
CƮ ↓ 7 %  
R
R
Effect of dolutegravir:  
Methadone ↔  
AUC ↓ 2 %  
Dolutegravir did not change  
methadone plasma  
Methadone  
JAN 2023  
concentrations to a clinically  
Initials………….  
Page 12 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
Cmax  
R
R
↔ 0 %  
relevant extent. No dose  
adjustment of methadone is  
necessary when co-administered  
with HETVIR 50.  
CƮ ↓ 1 %  
R
R
Abbreviations: ↑ = increase; ↓ = decrease; ↔ = no significant change; AUC =  
area under the concentration versus time curve; CRmaxR = maximum observed  
concentration, CRƮ R= concentration at the end of dosing interval.  
Additional information on special populations:  
No information available.  
Paediatric population:  
No information available.  
4.6  
Fertility, pregnancy and lactation  
Women of childbearing potential / Contraception in males and females:  
No information available.  
Pregnancy:  
Safe use during pregnancy and lactation has not been established. The effect of  
HETVIR 50 on human pregnancy is unknown. In reproductive toxicity studies in  
animals, dolutegravir was shown to cross the placenta.  
Breastfeeding:  
HIV infected women should not breastfeed their infants in order to avoid  
transmission of HIV. It is expected that HETVIR 50 will be secreted into human milk.  
Fertility:  
JAN 2023  
Initials………….  
Page 13 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
No information available.  
4.7  
Effects on ability to drive and use machines  
HETVIR 50 may cause side effects such as insomnia, headache, dizziness and  
fatigue. Patients should be advised not to drive or operate machines until it is  
established that their ability to perform such activities is not affected.  
The clinical status of the patient and the adverse event profile of HETVIR 50 should  
be borne in mind when considering the patient's ability to drive or operate  
machinery.  
4.8  
Undesirable effects  
Summary of the safety profile:  
Undesirable effects placed in order of frequent and less frequent.  
Tabulated summary of adverse reactions:  
Organ system  
Immune system  
disorders  
Frequent  
Less frequent  
Hypersensitivity (see  
SECTION 4.4), immune  
reconstitution  
---  
syndrome (see  
SECTION 4.4).  
---  
Psychiatric disorders  
Insomnia, abnormal  
dreams.  
Nervous system  
disorders  
Headache, dizziness.  
---  
Gastrointestinal  
disorders  
Nausea, diarrhoea,  
vomiting, flatulence,  
upper abdominal pain.  
Abdominal pain,  
abdominal discomfort.  
Hepato-biliary disorders ---  
Hepatitis.  
---  
Skin and subcutaneous  
tissue disorders  
Rash, pruritus.  
General disorders and  
administrative site  
conditions  
Fatigue.  
---  
The safety profile was similar across the treatment naive, treatment  
(and integrase naive) and integrase resistant patient populations.  
experienced  
JAN 2023  
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Page 14 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
Changes in laboratory chemistries:  
Increases in serum creatinine occurred within the first week of treatment with  
HETVIR 50 and remained stable through 48 weeks. In treatment naive patients a  
mean change from baseline of 9,96 μmol/L (range: -53 μmol/L to 54,8 μmol/L) was  
observed after 48 weeks of treatment. Creatinine increases were comparable by  
background NRTls and were similar in treatment experienced patients. These  
changes are not considered to be clinically relevant since they do not reflect a  
change in glomerular filtration rate (see Section 5.1 – Effects on Renal Function).  
Small increases in total bilirubin (without clinical jaundice) were observed on  
HETVIR 50 and raltegravir (but not efavirenz) arms in the programme. These  
changes are not considered clinically relevant as they likely reflect competition  
between HETVIR 50 and unconjugated bilirubin for a common clearance pathway  
(UGT1A1) (see Section 5.1 – Metabolism).  
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with  
exercise have also been reported with HETVIR 50 therapy.  
Description of selected adverse reactions:  
No information available.  
4.9  
Overdose  
Symptoms may be the exacerbation of side effects.  
Overdosage: 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 HETVIR 50.  
Treatment: If overdose occurs, the patient should be treated supportively with  
JAN 2023  
Initials………….  
Page 15 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
appropriate monitoring as necessary. As HETVIR 50 is highly bound to plasma  
proteins, it is unlikely that it will be significantly removed by dialysis.  
Additional information on special populations:  
No information available.  
Paediatric population:  
No information available.  
5
PHARMACOLOGICAL PROPERTIES  
A 20.2.8 Antiviral agents  
5.1  
Pharmacodynamic properties  
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  
(tR1/2R 71 hours).  
Resistance in vitro:  
Isolation from wild type HIV-1: Viruses highly resistant to dolutegravir were not  
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 (fold  
change) ≤ 4, 1 for strain IIIB, or E92Q with FC = 3,1 and G193E with FC = 3,2 for  
strain NL432. Additional passage of wildtype subtype B, C, and A/G viruses in the  
presence of dolutegravir selected for R263K, G118R, and S153T.  
JAN 2023  
Initials………….  
Page 16 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
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.  
Integrase 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.  
Integrase 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.  
Clinical Isolates from Raltegravir Treatment Virologic Failure Subjects: 705  
raltegravir resistant clinical isolates were analysed for susceptibility to dolutegravir  
using the Monogram Biosciences PhenoSense assay. Dolutegravir has a < 10 FC  
against 93,9 % of the 705 clinical isolates.  
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 (SPRING-1, SPRING-2 and SINGLE studies). In the  
SAILING study for treatment experienced (and integrase naive) patients (n = 354 in  
the dolutegravir arm), treatment emergent integrase resistance was observed in 2  
JAN 2023  
Initials………….  
Page 17 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
of 9 subjects with virologic failure. In both cases, a unique R263K integrase  
substitution was observed, with a maximum FC of 1,93.  
Resistance in vivo: integrase inhibitor resistant patients:  
The VIKING-3 study examined dolutegravir (plus optimised background therapy) in  
subjects with pre-existing INI resistance. Twenty-six subjects (26/114) experienced  
protocol defined virologic failure through to Week 24. Of these, 25 had paired  
baseline and PDVF resistance data for analysis and 13/25 (52 %) had treatment  
emergent mutations. Treatment emergent mutations or mixtures of mutations  
observed were E92Q (n = 2), T97A (n = 6), E138K/A (n = 4), G140S (n = 2), Y143H  
(n = 1), S147G (n=1), Q148H/K/R (n = 3), and N155H (n = 1). 11 of the 13 subjects  
with virus exhibiting treatment emergent mutations harboured 0148 pathway virus  
present at baseline or historically.  
Effects on Renal Function:  
The effect of dolutegravir on serum creatinine clearance (CrCL), glomerular filtration  
rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using  
para-aminohippurate (PAH) as the probe was evaluated in an open-label,  
randomised, 3 arm, parallel, placebo-controlled study in 37 healthy subjects, who  
were administered dolutegravir 50 mg once daily (n = 12), 50 mg twice daily (n =  
13) or placebo once daily (n = 12) for 14 days. A small decrease of 10-14 % in  
mean serum creatinine clearance (CrCL) 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.  
JAN 2023  
Initials………….  
Page 18 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
Paediatric population:  
no information available.  
5.2  
Pharmacokinetic properties  
Dolutegravir pharmacokinetics are similar between healthy and HIV-infected  
subjects. The PK variability of dolutegravir is between low to moderate. In Phase 1  
studies in healthy subjects, between-subject CVb % for AUC and CRmaxR ranged  
from ~ 20 to 40 % and CRƮR from 30 to 65 % across studies. The between-subject  
PK variability of dolutegravir was higher in HIV-infected subjects than healthy  
subjects. Within-subject variability (CVw %) is lower than between-subject  
variability.  
Absorption:  
Dolutegravir is absorbed following oral administration, with median TRmaxR at 2 to  
3 hours post dose for the tablet formulation. The linearity of dolutegravir  
pharmacokinetics is dependent on dose and fcfrormulation. Following oral  
administration of tablet formulations, dolutegravir exhibited non-linear  
pharmacokinetics with less than dose-proportional increases in plasma exposure  
from 2 to 100 mg; however, increase in dolutegravir exposure appears dose  
proportional from 25 mg to 50 mg.  
Dolutegravir may be administered with or without food. Food increased the extent  
and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir  
depends on meal content: low, moderate and high fat meals increased dolutegravir  
AUC (0-∞) by 34 %, 41 % and 66 %, increased CRmaxR by 46 %, 52 %, and 67  
%, prolonged TRmaxR to 3, 4, and 5 hours from 2 hours under fasted conditions,  
respectively. These increases are not clinically significant.  
JAN 2023  
Initials………….  
Page 19 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
The absolute bioavailability of dolutegravir has not been established.  
Distribution:  
Dolutegravir is highly bound (approximately 99,3 %) to human plasma proteins  
based on in vitro data. The apparent volume of distribution (following oral  
administration of suspension formulation, Vd/F) is estimated at 12,5 L. Binding of  
dolutegravir to plasma proteins was independent of concentration. Total blood and  
plasma medicine-related radioactivity concentration ratios averaged between 0,441  
to 0,535 indicating minimal association of radioactivity with blood cellular  
components. Free fraction of dolutegravir in plasma is estimated at approximately  
0,2 to 1,1 % in healthy subjects, approximately 0,4 to 0,5 % in subjects with  
moderate hepatic impairment, and 0,8 to 1,0 % in subjects with severe renal  
impairment and 0,5 % in HIV-1 infected patients. Dolutegravir is present in  
cerebrospinal fluid (CSF). In 13 treatment-naive subjects on a stable dolutegravir  
plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18  
ng/mL (comparable to unbound plasma concentration, and above the IC50);  
CSF:plasma concentration ratio of dolutegravir ranged from 0,11 to 0,66 %.  
Dolutegravir concentrations in CSF exceeded the IC50, supporting the median  
reduction from baseline in CSF HIV-1 RNA of 2,1 log after 2 weeks of therapy (see  
Section 5.2).  
Biotransformation:  
Dolutegravir is primarily metabolised via UGT1A1 with a minor CYP3A component  
(9,7 % of total dose administered in a human mass balance study). Dolutegravir is  
the predominant circulating compound in plasma; renal elimination of unchanged  
medicine is low (< 1 % of the dose). 53 % of total oral dose is excreted unchanged  
in the faeces. It is unknown if all or part of this is due to unabsorbed medicine or  
JAN 2023  
Initials………….  
Page 20 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
biliary excretion of the glucuronidate conjugate, which can be further degraded to  
form the parent compound in the gut lumen. 31 % of the total oral dose is excreted  
in the urine, represented by ether glucuronide of dolutegravir (18,9 % of total dose),  
N-dealkylation metabolite (3,6 % of total dose) and a metabolite formed by  
oxidation at the benzylic carbon (3,0 % of total dose).  
Elimination:  
Dolutegravir has a terminal half-life of ~ 14 hours and an apparent clearance (CL  
/F) of 0,56 L/hr.  
Linearity/non-linearity:  
No information available.  
Characteristics in specific groups of subjects or patients:  
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.  
Due to lack of clinical data, dolutegravir is not recommended for use in patients  
under 18 years of age (see Section 4.2).  
Table 1: Adolescent pharmacokinetic parameters  
Age/weight  
Dolutegravir  
Dose  
Dolutegravir Pharmacokinetic  
Parameter  
Estimates Geometric Mean (CV%)  
AUC  
R
Cmax  
R
µg/mL C24 µg/mL  
R
(0-24)  
R
µg.hr/mL  
JAN 2023  
Initials………….  
Page 21 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
12 to < 18  
years ≥ 40  
kga  
50 mg once  
dailya  
46 (43)  
3,49 (38)  
0,90 (59)  
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 (CrCL < 30 ml/min). No clinically important  
pharmacokinetic differences between subjects with severe renal impairment (CrCL  
< 30 ml/min) and matching healthy subjects were observed, AUC, CRmaxR, and  
CR24R 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) 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 effect of severe hepatic impairment on  
the pharmacokinetics of dolutegravir has not been studied.  
JAN 2023  
Initials………….  
Page 22 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
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 NR112 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.  
Pharmacokinetic/pharmacodynamic relationship(s):  
No information available.  
Paediatric population:  
No information.  
5.3  
Preclinical safety data  
No information available.  
JAN 2023  
Initials………….  
Page 23 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
6
PHARMACEUTICAL PARTICULARS  
6.1  
List of excipients  
Mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, sodium  
stearyl fumarate, Opadry II Pink 85F540088 (contains ferrosoferric oxide/black iron  
oxide, iron oxide red, iron oxide yellow, macrogol/PEG, polyvinyl alcohol, talc,  
titanium dioxide).  
Contains sugar (140.4 mg mannitol).  
6.2  
Incompatibilities  
No information available.  
6.3  
36 months.  
6.4  
Shelf life  
Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
Keep the blisters in the outer carton until required for use.  
KEEP OUT OF REACH OF CHILDREN.  
6.5  
Nature and contents of container  
HDPE bottles:  
•
28 film coated tablets are packed in a white opaque high density polyethylene  
(HDPE) bottle with a white opaque child resistant plastic cap with pulp liner.  
30 film coated tablets are packed in a white opaque high density polyethylene  
(HDPE) bottle with a white opaque child resistant plastic cap with pulp liner.  
•
Blister strips:  
Plain aluminium laminate/silver aluminium foil blister strips containing 10 tablets  
•
per blister; 3 or 10 blister strips enclosed in a carton box.  
JAN 2023  
Initials………….  
Page 24 of 25  
Applicant/HCR: Hetero Drugs South Africa (Pty) Ltd  
Product name: HETVIR 50  
Dosage form and strength: Film-coated, Dolutegravir sodium equivalent to 50 mg Dolutegravir  
6.6  
Special precautions for disposal <and other handling>  
No information available.  
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  
8
9
REGISTRATION NUMBER(S)  
HETVIR 50: 52/20.2.8/0003.001  
DATE OF FIRST AUTHORISATION/RENEWAL OF THE  
AUTHORISATION  
11 June 2018  
10  
DATE OF REVISION OF THE TEXT  
31 January 2023.  
JAN 2023  
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