Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
PROFFESIONAL INFORMATION for FOVIREM (FILM-COATED TABLET)  
SCHEDULING STATUS  
S4  
PROPRIETARY NAME AND DOSAGE FORM  
FOVIREM (Film-coated tablet)  
COMPOSITION  
Each film-coated tablet contains: 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (equivalent to  
245 mg of tenofovir disoproxil) as the active ingredients.  
The other ingredients are croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline  
cellulose, Opadry II Blue and pregelatinised starch.  
Contains lactose monohydrate.  
WARNING:  
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES,  
HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR IN  
COMBINATION WITH OTHER ANTIRETROVIRALS (SEE "WARNINGS AND SPECIAL  
PRECAUTIONS"). THE COMBINATION TABLET IS NOT INDICATED FOR THE TREATMENT OF  
CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF THE  
COMBINATION TABLET HAS NOT BEEN ESTABLISHED IN PATIENTS COINFECTED WITH HBV  
AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN  
PATIENTS WHO HAVE DISCONTINUED EMTRICITABINE (200 MG) OR TENOFOVIR.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
HEPATIC FUNCTIONS SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND  
LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE  
THE COMBINAION TABLET AND ARE COINFECTED WITH HIV AND HBV. IF APPROPRIATE,  
INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED {SEE WARNINGS AND  
SPECIAL PRECAUTIONS).  
PHARMACOLOGICAL CLASSIFICATION  
A.20.2. Antiviral Agents.  
PHARMACOLOGICAL ACTION  
Pharmacodynamic properties:  
Emtricitabine: Emtricitabine, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular  
enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'- triphosphate inhibits the activity of the HIV-1  
reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by  
being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is  
a weak inhibitor of mammalian DNA polymerase  
,  
,
and mitochondrial DNA polymerase  
.  
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate also known as tenofovir DF is an acyclic nucleoside  
phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester  
hydrolysis for conversion to tenofovir and subsequent phosphorylation’s by cellular enzymes to form tenofovir  
diphosphate.  
Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-  
triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of  
mammalian DNA Polymerases  
,
,
and mitochondrial DNA polymerase  
.  
Resistance:  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Emtricitabine and tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to the combination of  
emtricitabine and tenofovir have been selected in vitro. Genotypic analysis of these isolates identified the M184I/V  
and/or K65R amino acid substitutions in the viral RT.  
Emtricitabine: Emtricitabine-resistant isolates of· HIV have been selected in vitro. Genotypic analysis of these  
isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV RT gene at  
codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).  
Emtricitabine- resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in  
combination with other antiretroviral agents. In a clinical study, viral isolates from 6/16 (37,5 %) treatment-naive  
patients with virologic failure showed >20-fold reduced susceptibility to emtricitabine. Genotypic analysis of these  
isolates showed that the resistance was due to M184V/I mutations in the HIV RT gene.  
Tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro.  
These viruses expressed a K65R mutation in RT and showed 2 - 4 fold reduction in susceptibility to tenofovir.  
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir in  
combination with certain antiretroviral agents.  
In treatment-naȉve patients, 8/47 (17 %) isolates from patients failing tenofovir + lamivudine + efavirenz through week  
144 showed > 1,4 fold (median 3,7) reduced susceptibility in vitro to tenofovir. In treatment-experienced patients,  
14/304 (5 %) isolates from patients failing tenofovir through week 96 showed > 1,4 fold (median 2,7) reduced  
susceptibility to tenofovir.  
Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid  
substitution.  
Cross-resistance:  
Emtricitabine and tenofovir disoproxil fumarate: Cross-resistance among certain nucleoside reverse transcriptase  
inhibitors (NRTls) has been recognized. The M184V/l and/or K65R substitutions selected in vitro by the combination of  
emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance  
among these medicines may occur in patients whose virus harbours either or both of these amino acid substitutions.  
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but  
retained susceptibility in vitro to didanosine, stavudine, tenofovir, zidovudine, and NNRTls (delavirdine, efavirenz, and  
nevirapine). Isolates from heavily treatment-experienced patients containing the M184V/I amino acid substitution in  
the context of other NRTI resistance-associated substitutions may retain susceptibility to tenofovir. HIV-1 isolates  
containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated  
reduced susceptibility to inhibition by emtricitabine. Viruses harbouring mutations conferring reduced susceptibility to  
stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) ordidanosine (L74V) remained sensitive  
to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTls was susceptible to  
emtricitabine.  
Tenofovir disoproxil fumarate: HIV-1 isolates from patients (N = 20) whose HIV-1 expressed a mean of 3’  
zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) showed a  
3,1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion  
mutation in the RT showed reduced susceptibility to tenofovir.  
Antiviral Activity:  
Emtricitabine and tenofovir disoproxil fumarate: In combination studies evaluating the in vitro antiviral activity of  
emtricitabine and tenofovir together, synergistic antiviral effects were observed.  
Pharmacokinetic properties:  
Pharmacokinetics in Adults  
One tenofovir and emtricitabine combination tablet was bioequivalent to one emtricitabine capsule (200 mg) plus one  
tenofovir disoproxil fumarate 300 mg tablet following single- dose administration to fasting healthy subjects (N=39).  
Emtricitabine: The pharmacokinetic properties of emtricitabine are summarised in Table 1.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Following oral administration of emtricitabine (200 mg), emtricitabine is rapidly absorbed with peak plasma  
concentrations occurring at 1 - 2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is < 4 %  
and is independent of concentration over the range of 0,02 - 200 µg/mL. Following administration of radio-labelled  
emtricitabine, approximately 86 % is recovered in the urine and 13 % is recovered as metabolites. The metabolites of  
emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a  
combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine (200 mg),  
the plasma emtricitabine half-life is approximately 10 hours.  
Tenofovir disoproxil fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarised in  
Table 1.  
Following oral administration of tenofovir disoproxil fumarate, maximum tenofovir serum concentrations are achieved  
in 1,0 ± 0,4 hour. In vitro binding of tenofovir to human plasma proteins is< 0,7 % and is independent of concentration  
over the range of 0,01 - 25 µg/ml. Approximately 70 - 80 % of the intravenous dose of tenofovir is recovered as  
unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular  
secretion. Following a single oral dose of tenofovir disoproxil fumarate, the terminal elimination half-life is  
approximately 17 hours.  
Table 1 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults1  
Emtricitabine  
Tenofovir  
Fasted Oral  
92 (83,1 -106,4)  
25 (NC - 45,0)  
2
Bioavailability (%)  
10 (7,4-18,0)  
17 (12,0-25,7)  
Plasma Terminal Elimination  
2
Half-Life (hr)  
3
4
0,30 ± 0,09  
2,29 ± 0,69  
Cmax (ug/ml)  
1,8 ± 0,72  
3
4
AUC (ug - hr/ml)  
10,0 ± 3,12  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
3
302 ± 94  
213 ± 89  
1043 ± 115  
243 ± 33  
CL/F (ml/min)  
3
Cl rena1 (ml/min)  
1.  
2.  
3.  
4.  
NC = Not calculated  
Median (range)  
Mean (± SD)  
Data presented as steady state values.  
Effects of Food on Oral Absorption  
The combination tablet may be administered with or without food. Administration of the tenofovir and emtricitabine  
combination tablet following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat)  
delayed the time of tenofovir Cmax by approximately 0,75 hour. The mean increases in tenofovir AUC and Cmax were  
approximately 35 % and 15 %, respectively, when administered with a high fat or light meal, compared to  
administration in the fasted state. In previous safety and efficacy studies, tenofovir was taken under fed conditions.  
Emtricitabine systemic exposures (AUC and Cmax) were unaffected when the combination tablet was administered with  
either a high fat or a light meal.  
Special Populations:  
Paediatric and Geriatric Patients: Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in  
children(< 18 years) or in the elderly(> 65 years) (see WARNINGS AND SPECIAL PRECAUTIONS, Paediatric Use,  
Geriatric Use).  
Patients with Impaired Renal Function: The pharmacokinetics of emtricitabine and tenofovir are altered in patients  
with renal impairment (see WARNINGS AND SPECIAL PRECAUTIONS, Renal Impairment). In patients with  
creatinine clearance< 50 ml/min, Cmax, and AUC0-of emtricitabine and tenofovir were increased. It is recommended  
that the dosing interval for the combination tablet be modified in patients with creatinine clearance 30 - 49 ml/min. The  
combination tablet (emtricitabine and tenofovir) should not be used in patients with creatinine clearance < 30 ml/min  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
and in patients with end-stage renal disease requiring dialysis (see WARNINGS AND SPECIAL PRECAUTIONS,  
Renal Impairment).  
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil  
fumarate 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. The pharmacokinetics of the FOVIREM have not been studied in patients with hepatic impairment.  
INDICATIONS  
FOVIREM is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase  
inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.  
CONTRA-INDICATIONS  
FOVIREM is contra-indicated:  
•
•
•
In patients with previously demonstrated hypersensitivity to any of the components of the product.  
Moderate to severe uncontrolled renal failure.  
Pregnancy and lactation.  
WARNINGS AND SPECIAL PRECAUTIONS  
•
•
There are no study results demonstrating the effect of FOVIREM on clinical progression of HIV-1.  
It is not recommended that FOVIREM be used as a component of a triple nucleoside regimen.  
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.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
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 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). 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 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, cytomegalovirus retinitis,  
and cryptococcal meningitis.  
Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. 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) 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.  
Bone Effects  
Tenofovir disoproxil fumarate: In a study of treatment naive patients, decreases from baseline in bone mineral  
density (BMD) were seen at the lumbar spine and hip in both arms of the study. There was a significantly greater  
mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving tenofovir disoproxil  
fumarate + lamivudine + efavirenz (-2,2 % ± 3,9) compared with patients receiving stavudine + lamivudine +  
efavirenz (-1,0 % ± 4,6). Changes in BMD at the hip were similar between the two treatment groups (-2,8 % ± 3,5 in  
the tenofovir disoproxil fumarate group vs. -2,4 % ± 4,5 in the stavudine group). In both groups, the majority of  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
the reduction in BMD occurred in the first 24-48 weeks of the study and this reduction was sustained through week  
144.  
Twenty-eight percent of tenofovir disoproxil fumarate -treated patients vs. 21 % of the stavudine-treated patients lost  
at least 5 % of BMD at the spine or 7 % of BMD at the hip. Clinically relevant fractures (excluding fingers and toes)  
were reported in patients in the tenofovir disoproxil fumarate group and stavudine group. In addition, there were  
significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum  
osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the tenofovir disoproxil fumarate group relative to the  
stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels  
were also higher in the tenofovir disoproxil fumarate group relative to the stavudine group. Except for bone specific  
alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of tenofovir  
disoproxil fumarate - associated changes in BMD and biochemical markers on long-term bone health and future  
fracture risk are unknown.  
Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of  
tenofovir DF (see SIDE-EFFECTS).  
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.  
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.  
Opportunistic infections  
Patients receiving FOVIREM should be advised that they may continue to develop opportunistic infections and other  
complications of HIV infection, and therefore they should remain under close observation by healthcare professionals  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts  
needs to be done.  
The risk of HIV transmission to others  
Patients should be advised that current antiretroviral therapy, including FOVIREM, does not prevent the risk of  
transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue  
to be employed.  
Lactic acidosis / hyperlactataemia  
Use of FOVIREM can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction.  
Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss.  
In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal< 2 mmol/f) and the  
serum bicarbonate and respond as follows:  
•
•
Lactate 2-5 mmol/f with minimum symptoms: switch to agents that are less likely to cause lactic acidosis.  
Lactate 5-10 mmol/f with symptoms and/or with reduced standard bicarbonate: Stop NRTls and change treatment  
option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis.  
Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism.  
Lactate > 10 mmol/t STOP all therapy (80 % mortality).  
•
•
The above lactate values may not be applicable to paediatric patients.  
Caution should be exercised when FOVIREM to patients with known risk factors for liver disease.  
Treatment with FOVIREM should be suspended in any patient who develops clinical or laboratory findings suggestive  
of lactic acidosis or hepatotoxicity.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Mitochondrial dysfunction  
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of  
mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero  
and/or post-natally to nucleoside analogues.  
Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include  
haematological disorders (anaemia, neutropenia), and peripheral neuropathy.  
Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour).  
It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to  
nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-  
up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.  
Pancreatitis  
Pancreatitis has been observed in some patients receiving FOVIREM.  
Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated  
biochemical markers. Discontinue use of FOVIREM 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 FOVIREM is increased due to decreased  
clearance. The dose of FOVIREM should therefore be adjusted (see DOSAGE AND DIRECTION FOR USE).  
Emtricitabine and tenofovir are principally eliminated by the kidney. Dosing interval adjustment of FOVIREM is  
recommended in all patients with creatinine clearance 30 - 49 ml/min, (see DOSAGE AND DIRECTIONS FOR USE).  
FOVIREM should not be administered to patients with creatine clearance< 30 ml/min or patients requiring  
haemodialysis.  
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe  
hypophosphatemia), has been reported in association with the use of tenofovir (see SIDE EFFECTS). The majority of  
these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents,  
however, some cases occurred in patients without identified risk factors.  
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Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
FOVIREM should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a  
history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for  
changes in serum creatinine and phosphorus.  
Liver disease  
Use of FOVIREM can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety  
and efficacy of FOVIREM has not been established in patients with significant underlying liver disorders/diseases. In  
case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant package inserts for these  
medicines.  
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. If there is evidence of  
worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.  
Patients with HIV and hepatitis B or C virus co-infection  
Patients with chronic hepatitis B or C and treated with antiretroviral therapy are 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 package inserts for these  
medicines.  
Patients co-infected with HIV and HBV who FOVIREM should be closely monitored with both clinical and laboratory  
follow-up after stopping treatment.  
In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-  
treatment exacerbation of hepatitis may lead to hepatic decompensation.  
Discontinuation of FOVIREM therapy in patients co-infected with HIV and HBV may be associated with severe, acute  
exacerbations of hepatitis.  
It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating  
antiretroviral therapy. FOVIREM is not indicated for the treatment of (chronic HBV infection and the safety and efficacy  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
of FOVIREM have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of  
hepatitis B have been reported in patients after the discontinuation of emtricitabine (200 mg) and tenofovir disoproxil  
fumarate. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several  
months in patients who discontinue FOVIREM and are co-infected with HIV and HBV.  
Paediatric Use  
Safety and effectiveness in paediatric patients have not been established.  
Geriatric Use  
Clinical studies of emtricitabine (200 mg) or tenofovir disoproxil fumarate did not include sufficient numbers of subjects  
aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for  
the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac  
function, and of concomitant disease or other medicine therapy.  
Effects on ability to drive and use machines:  
FOVIREM may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they  
experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.  
Lactose:  
FOVIREM contains lactose, therefore it should not be used in cases of congenital galactosaemia, glucose and  
galactose malabsorption or lactose deficiency syndromes (rare metabolic diseases).  
INTERACTIONS  
FOVIREM: No medicine interaction studies have been conducted using FOVIREM tablets.  
Emtricitabine and tenofovir disoproxil fumarate: The steady state pharmacokinetics of emtricitabine and tenofovir  
were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent  
dosed alone.  
In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450 mediated interactions  
involving emtricitabine and tenofovir with other medicinal products is low.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active  
tubular secretion. No interactions due to competition for renal excretion have been observed; however,  
coadministration of FOVIREM with medicines that are eliminated by active tubular secretion may increase  
concentrations of emtricitabine, tenofovir, and/or the coadministered medicine.  
Medicines that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.  
No clinically significant interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine,  
and tenofovir disoproxil fumarate (see Tables 2 and 3). Similarly, no clinically significant interactions have been  
observed between tenofovir disoproxil fumarate and abacavir, adefovir dipivoxil, ribavirin, efavirenz, emtricitabine,  
indinavir, lamivudine, lopinavir/ritonavir, methadone and oral contraceptives in studies conducted in healthy volunteers  
(see Tables 4 and 5).  
Table 2  
Medicine Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the  
Coadministered Medicine1  
% Change of Emtricitabine  
Pharmacokinetic Parameters2  
Dose of Co-  
administered  
Medicine (mg)  
Co-administered  
Medicine  
Emtricitabine Dose  
(mg)  
(90% CI)  
AUC  
N
Cmax  
Cmin  
↑20  
300 once daily x 7  
days  
200 once daily x 7  
days  
Tenofovir DF  
17  
-
-
(↑12 to  
↑29)  
NA  
Indinavir  
Famciclovir  
Stavudine  
800 x 1  
500 x 1  
40 x 1  
200 x 1  
200 x 1  
200 x 1  
12  
12  
6
-
-
-
-
-
-
NA  
NA  
1.  
1. All interaction studies conducted in healthy volunteers.  
2. 2. ↑ = Increase; ↓ = Decrease; — = No Effect; NA = Not Applicable  
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20 May 2022 (esub0002-dvp)  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Table 3  
Medicine Interactions: Changes in Pharmacokinetic Parameters for Coadministered Medicine in the Presence  
of Emtricitabine1  
%
Change of Co-  
Co- administered  
Medicine  
Dose of Co-  
administered  
Medicine (mg)  
Emtricitabine Dose  
(mg)  
N
administered Medicine  
Pharmacokinetic  
Parameters2 (90% Cl)  
AUC  
Cmax  
Cmin  
-
Tenofovir DF  
300 once  
daily x 7 days  
800 X 1  
200 once  
daily x 7 days  
200 X 1  
17  
-
-
lndinavir  
12  
12  
6
-
-
-
-
NA  
NA  
NA  
Famciclovir  
Stavudine  
500 X 1  
200 X 1  
-
-
40 X 1  
200 X 1  
1. All interaction studies conducted in healthy volunteers.  
2. ↑ = Increase; ↓ = Decrease; - = No Effect; NA= Not Applicable  
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Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Table 4  
Medicine Interactions: Changes in Pharmacokinetic Parameters for Tenofovir1 in the Presence of the  
Coadministered Medicine  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
% Change of Tenofovir Pharmacokinetic  
Dose of Co-  
Parameters2 (90% CI)  
Co-administered  
administered  
Medicine (mg)  
N
Medicine  
Cmax  
AUC  
Cmin  
Abacavir  
300 once  
8
-
-
NC  
Adefovir dipivoxil  
10 once  
22  
-
-
NC  
400 once daily x 14  
days  
↑14  
↑24  
↑22  
Atazanavir3  
33  
25  
14  
29  
17  
13  
15  
24  
(↑8 to ↑20)  
(↑21 to ↑28)  
(↑15 to ↑30)  
Didanosine (enteric-  
coated)  
400 once  
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
250 or 400 once daily  
x 7 days  
Didanosine (buffered)  
Efavirenz  
600 once daily x 14  
days  
200 once daily x 7  
days  
Emtricitabine  
Indinavir  
800 three times daily  
x 7 days  
↑14  
(↓3 to ↑33)  
150 twice daily x 7  
days  
Lamivudine  
-
-
Lopinavir/  
Ritonavir  
400/100 twice daily x  
14 days  
↑32  
↑51  
(↑25 to ↑38)  
(↑37 to ↑66)  
1. Patients received tenofovir disoproxil fumarate 300 mg once daily.  
2. ↑ = Increase; ↓ = Decrease; - = No Effect; NC= Not Calculated  
3. REYATAZ® US Prescribing ir.iformation (Bristol-Myers Squibb)  
Table 5  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Interactions: Changes in Pharmacokinetic Parameters for Coadministered Medicine in the Presence of  
Tenofovir  
Dose of Co-administered  
Medicine (mg)  
N
% Change of Co-administered Medicine  
Pharmacokinetic Parameters1 (90% Cl)  
Co-  
administered Medicine  
AUC  
Cm1n  
Cmax  
12  
1 to  
Abacavir  
300 once  
8
↑
NA  
-
(
↑
↑
26)  
10 once  
22  
34  
NA  
Adefovir  
-
-
dipivoxil  
Atazanavir2  
400 once daily x 14 days  
↓
21  
↓
25  
30 to  
19)  
↓
40  
48 to ↓ 32)  
(
↓
27 to  
↓
↑
(
↓
(
↓
14)  
Atazanavir 2  
Atazanavir/Ritonavir 300/100  
once daily x 42 days  
10  
↓
28  
50 to  
↓
253  
42 to  
↓
233  
(
5)  
↓
(
3)  
↓
↑
(
↓
46 to  
↓
10)  
600 once daily x 14 days  
200 once daily x 7 days  
30  
17  
-
-
-
-
Efavirenz  
-
Emtricitabine  
↓
20  
12 to  
(
↓
↓ 29)  
lndinavir  
800 three times daily x 7 days  
150 twice daily x 7 days  
12  
15  
24  
-
-
-
-
-
-
↓
11  
(
↓
30 to  
↓
12)  
Lamivudine  
Lopinavir  
↓
24  
34 to  
(
↓
↓
12)  
Lopinavir/Ritonavir  
-
400/100 twice daily x 14 days  
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20 May 2022 (esub0002-dvp)  
Page 18 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Methadone 4  
40 - 110 once daily x 14 days5  
13  
20  
-
-
-
-
-
-
Oral Contraceptives6  
Ethinyl estradiol/  
Norgestimate (Ortho-  
Tricyclen®)  
Once daily x 7 days  
Ribavirin  
Ritonavir  
600 once  
22  
24  
NA  
-
-
-
-
-
Lopinavir/Ritonavir 400/100  
twice daily x14days  
1. ↑ = Increase; ↑ = Decrease; - = No Effect; NA= Not Applicable  
2. REYATAZ® US Prescribing information (Bristol-Myers Squibb)  
3. In HIV-infected patients, addition of tenofovir DF 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.  
4. R-(active), S-and total methadone exposures were equivalent when dosed alone or with tenofovir  
disoproxil fumarate.  
5. Individual subjects were maintained on their stable methadone dose. No pharmacodynamics alterations  
(opiate toxicity or withdrawal signs or symptoms) were reported.  
6. Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were  
equivalent when dosed alone or with tenofovir disoproxil fumarate.  
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral  
contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in  
previous studies, indicating lack of clinically significant medicine interactions between these agents and tenofovir.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of  
didanosine that may be of clinical significance.  
Table 6 summarises the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine.  
Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules  
significantly increase the Cmax and AUC of didanosine.  
When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic  
exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted  
conditions. The mechanism of this interaction is unknown.  
Table 6  
Medicine Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir disoproxil  
fumarate  
1
Tenofovir Method of  
N
%
Difference (90% Cl} vs.  
Didanosine Dose (mg}/  
Method of  
2
Didanosine 400 mg Alone,  
Administration  
Administration2  
3
Fasted  
AUC  
Cmax  
Buffered tablets  
4
14  
Fasted 1 hour after  
didanosine  
↑
28  
↑
44  
400 once daily  
(
↑
11 to  
↑
48)  
(
↑
31 to  
↑
↑
59)  
67)  
x 7 days  
Enteric-coated capsules  
400 once, fasted  
26  
26  
28  
With food, 2 hrs  
after didanosine  
↑
↑
48  
↑
48  
↑
25 to  
↑
76)  
(
31 to  
400 once, with food  
250 once, fasted  
Simultaneously with  
didanosine  
↑
64  
↑
60  
↑
( 44 to  
↑
79)  
(
↑
41 to  
↑
89)  
3)  
-
With food, 2 hrs after  
didanosine  
↑
10  
(
↑
22 to  
↑
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20 May 2022 (esub0002-dvp)  
Page 20 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
250 once, fasted  
Simultaneously with  
didanosine  
28  
-
↑
14  
(0 to  
↑
31)  
28  
250 once, with food  
Simultaneously with  
didanosine  
↑
29  
↑
11  
23 to  
(
↑
39 to  
↑
18)  
(
↑
↑
2)  
1. See Precautions regarding use of didanosine with tenofovir disoproxil fumarate.  
2. Administration with food was with a light meal (~373 kcal, 20 % fat).  
3. Increase= i Decrease= 1 No difference= -  
4. Includes 4 subjects weighing <60 kg receiving ddl 250 mg  
Tenofovir disoproxil fumarate: when tenofovir disoproxil fumarate was administered with didanosine the Cmax and  
AUC of didanosine administered as either the buffered or enteric- coated formulation increased significantly (see Table  
6). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-  
associated adverse events, including pancreatitis, and neuropathy. In adults weighing> 60 kg, the didanosine dose  
should be reduced to 250 mg when it is coadministered with FOVIREM. Data are not available to recommend a dose  
adjustment of didanosine for patients weighing< 60 kg. When coadministered FOVIREM and didanosine may be taken  
under fasted conditions or with a light meal(< 400 kcal, 20 % fat).  
Coadministration of didanosine buffered tablet formulation with FOVIREM should be under fasted conditions.  
Co-administration of FOVIREM and didanosine should be undertaken with caution and patients receiving this  
combination should be monitored closely for didanosine-associated adverse events.  
Didanosine should be discontinued in patients who develop didanosine-associated adverse events.  
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this  
interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and FOVIREM should be monitored for  
FOVIREM-associated adverse events.  
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Page 21 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
FOVIREM should be discontinued in patients who develop FOVIREM-associated adverse events.Tenofovir decreases  
the AUC and Cmin of atazanavir. When coadministered with FOVIREM, it is recommended that atazanavir 300 mg is  
given with ritonavir 100 mg.  
Atazanavir without ritonavir should not be coadministered with FOVIREM.  
Emtricitabine and tenofovir disoproxil fumarate: Since Emtricitabine and tenofovir are primarily eliminated by the  
kidneys, coadministration of FOVIREM with medicines that reduce renal functions or compete for active tubular  
secretion may increase serum concentrations of emtricitabine, tenofovir and/or other renally eliminated medicines.  
Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and  
valganciclovir.  
FOVIREM is fixed dose combination of Emtricitabine and tenofovir disoproxil fumarate FOVIREM should not be  
coadministered with emtricitabine (200 mg) or tenofovir. Due to similarities between emtricitabine and lamivudine.  
FOVIREM should not be coadministered with other medicines containing lamivudine, including lamivudine and  
zidovudine coformulation, lamivudine for HIV, lamivudine for HBV, abacavir sulfate and lamivudine co-formulation or  
abacavir sulfate, lamivudine and zidovudine co-formulation.  
PREGNANCY AND LACTATION  
Emtricitabine: The incidence of foetal variations and malformations was not increased in embryofoetal toxicity studies  
performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately  
120-fold higher than human exposures at the recommended daily dose.  
Tenofovir disoproxil fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and  
19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or  
harm to the foetus due to tenofovir.  
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction  
studies are not always predictive of human response, FOVIREM should not be used during pregnancy (See  
CONTRA-INDICATIONS).  
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Page 22 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Nursing Mothers: HIV-infected mothers should not breast-feed their infants, to avoid risking postnatal transmission of  
HIV. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted  
in human milk.  
It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV transmission  
and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if  
they are receiving FOVIREM.  
DOSAGE AND DIRECTIONS FOR USE  
The dose of FOVIREM is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate)  
once daily taken orally with or without food.  
Dose Adjustment for Renal Impairment:  
Significantly increased exposure occurred when emtricitabine (200 mg) or tenofovir disoproxil fumarate were  
administered to patients with moderate to severe renal impairment (see CONTRA-INDICATIONS).  
SIDE-EFFECTS  
Blood and the lymphatic system disorders:  
Frequent: Neutropenia.  
Less frequent: Anaemia.  
Immune system disorders:  
Frequent: Allergic reaction, angioedoema.  
Metabolism and nutrition disorders:  
Frequent: Hypertriglyceridaemia, hyperglycaemia, hypophosphataemia, lactic acidosis, lipodystrophy.  
Less frequent: Hypokalaemia  
Psychiatric disorders:  
Frequent: Insomnia, abnormal dreams.  
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Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
Respiratory disorders:  
The following side-effects have been reported and frequencies are unknown: Chest pain, pneumonia, dyspnea,  
increased cough and rhinitis.  
Nervous system disorders:  
Frequent: Dizziness, headache.  
Gastrointestinal disorders:  
Frequent: Diarrhoea, nausea, vomiting, flatulence, dyspepsia, abdominal pain, elevated amylase, elevated lipase.  
Less frequent: Pancreatitis.  
Hepatobiliary disorders:  
Frequent: Hyperbilirubinaemia, raised transaminase, increased serum alanine aminotransferase (ALT), increase  
serum aspartate aminotransferase (AST).  
The following side-effects have been reported but frequencies are unknown: Hepatitis, hepatic steatosis.  
Skin and subcutaneous system disorders:  
Frequent: Rash, pruritus, maculopapular rash, urticaria, vesiculousbullous rash, pustular rash, skin discolouration.  
Musculoskeletal and connective tissue disorders:  
Frequent: Elevated creatine kinase.  
Less frequent: Rhabdomyolysis, muscular weakness.  
The following side-effects have been reported but frequencies are unknown: Myopathy, osteomalacia.  
Renal and urinary disorders:  
The following side-effects have been reported but frequencies are unknown: Increased creatinine, renal insufficiency,  
renal failure, acute and chronic renal failure, Fanconi syndrome, proximal renal tubulopathy, nephrogenic diabetes  
insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis.  
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20 May 2022 (esub0002-dvp)  
Page 24 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
General disorders:  
Frequent: Pain, asthenia.  
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT  
If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied  
as necessary.  
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine (200  
mg).  
Haemodialysis treatment removes approximately 30 % of the emtricitabine dose over a 3- hour dialysis period starting  
within 1,5 hours of emtricitabine dosing (blood flow rate of 400 ml/min and a dialysate flow rate of 600 ml/min). It is not  
known whether emtricitabine can be removed by peritoneal dialysis.  
Tenofovir disoproxil fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir 300  
mg is available. The effects of higher doses are not known.  
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.  
IDENTIFICATION  
Fovirem is a blue, capsule shaped, film coated tablets, debossed with 'H' on one side and '124' on the other side.  
PRESENTATION  
FOVIREM is packed in high density polypropylene (HDPE) bottle pack comprising of white opaque HDPE bottle with  
a white opaque child resistant plastic cap with desiccant in 30's and 60's pack.  
The HDPE containers are packed into a carton cardboard box.  
Not all pack sizes may be marketed.  
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20 May 2022 (esub0002-dvp)  
Page 25 of 26  
Applicant /PHCR: Hetero Drugs South Africa (Pty) Ltd.  
Product Proprietary name: Fovirem, Film – coated Tablet  
Dosage form and strength: Emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg  
STORAGE INSTRUCTIONS  
Store at or below 30 °C.  
Do not use if seal over bottle opening is broken or missing.  
KEEP OUT OF REACH OF CHILDREN.  
REGISTRATION NUMBER  
49/20.2.8/0100  
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No. 2, First Floor,  
74 Waterfall Drive, Midrand,  
2066  
DATE OF PUBLICATION OF THE PACKAGE INSERT  
29 September 2017.  
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20 May 2022 (esub0002-dvp)  
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