Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
APPROVED PROFESSIONAL INFORMATION – HETRIPCO  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
HETRIPCO 600 mg, 200 mg and 300 mg (film coated tablets)  
WARNING:  
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL  
CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE  
OR IN COMBINATION WITH OTHER ANTI-RETROVIRALS.  
HETRIPCO IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS  
(HBV) INFECTION AND THE SAFETY AND EFFICACY OF HETRIPCO HAVE NOT BEEN  
ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE  
EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE  
DISCONTINUED EMTRICITABINE OR TENOFOVIR, WHICH ARE COMPONENTS OF  
HETRIPCO. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH  
CLINICAL AND LABORATORY FOLLOW-UP FOR ATLEAST SEVERAL MONTHS IN  
PATIENTS WHO ARE CO-INFECTED WITH HIV AND HBV AND DISCONTINUE HETRIPCO.  
IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED.  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil (which is equivalent to 245 mg of tenofovir).  
HETRIPCO is sugar free.  
Initials_____________  
November 2021  
Page 1 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
This medicine contains 12 mg Sodium Lauryl Sulphate per tablet, essentially ‘sodium-free’.  
For full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
Film coated tablets, pink coloured, capsule shaped, debossed with “H” on one side and “128” on the other  
side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
HETRIPCO is indicated for use alone as a complete regimen or in combination with other anti-retroviral  
medicines for the treatment of HIV-1 infection in adults.  
4.2 Posology and method of administration  
Posology  
Adults  
The dose of HETRIPCO is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may  
improve the tolerability of nervous system symptoms.  
Special populations  
Patients weighing less than 40 kg and presenting with long-term neuropsychiatric effects  
A dose reduction and therapeutic drug monitoring of efavirenz should be considered in patients weighing  
less than 40 kg and presenting with long-term neuropsychiatric effects such as ataxia, encephalopathy,  
hyper- somnolence and coma. As a dose reduction of efavirenz, only, is not possible with HETRIPCO, these  
patients should be treated with separate formulations of the active ingredients.  
Elderly  
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November 2021  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
HETRIPCO should be administered with caution to elderly patients (see Section 4.4).  
Renal impairment  
Because HETRIPCO is a fixed-dose combination, it should not be prescribed for patients requiring dosage  
adjustment such as those with moderate or severe renal impairment (creatinine clearance less than 50  
ml/min) (see Sections 4.4 and 5.2).  
Hepatic impairment  
The pharmacokinetics of HETRIPCO have not been studied in patients with hepatic impairment. HETRIPCO  
is contraindicated in patients with severe hepatic impairment (see Section 4.3).  
Paediatric population  
HETRIPCO is not recommended for use in patients under 18 years of age (see Section 5.2).  
Method of Administration  
HETRIPCO tablets should be swallowed whole with water.  
HETRIPCO is a coated tablet. It should not be chewed or broken.  
4.3 Contraindications  
•
Hypersensitivity to efavirenz, emtricitabine or tenofovir disoproxil or any of the ingredients of  
HETRIPCO, including the excipients.  
•
HETRIPCO should not be administered concurrently with astemizole, bepridil, cisapride,  
midazolam, pimozide, triazolam or ergot derivatives because competition for CYP3A4 by  
efavirenz could result in inhibition of metabolism of these medicines and create the potential for  
serious and/or life-threatening adverse events (e.g. cardiac dysrhythmias, prolonged sedation or  
respiratory depression). HETRIPCO should not be administered concurrently with voriconazole  
Initials_____________  
November 2021  
Page 3 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
because efavirenz significantly decreases voriconazole plasma concentrations (see Section 4.5).  
•
HETRIPCO is contraindicated in patients with moderate to severe renal impairment [Creatinine  
Clearance less than 50 ml/min (see Sections 4.4 and 5.2).  
•
•
HETRIPCO is contraindicated in patients with severe hepatic impairment.  
HETRIPCO is contraindicated in patients with a history of previous liver injury/failure with  
efavirenz containing antiretroviral treatment (ARV).  
•
Pregnancy and lactation (see Section 4.6).  
4.4 Special warnings and precautions for use  
Lactic Acidosis/Severe Hepatomegaly with Steatosis  
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the  
use of nucleoside analogues alone or in combination with other antiretrovirals. A majority of these cases  
have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution  
should be exercised when administering nucleoside analogues to any patient with known risk factors for liver  
disease; however, cases have also been reported in patients with no known risk factors. Treatment with  
HETRIPCO should be suspended in any patient who develops clinical or laboratory findings suggestive of  
lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the  
absence of marked transaminase elevations).  
Routine testing of serum lactate levels in asymptomatic patients on antiretroviral is not recommended.  
Measurement of serum lactate levels is recommended only for patients presenting with clinical signs or  
symptoms consistent with lactic acidosis  
Lactate 2 to 5 mmol/L: monitor regularly and be alert tor clinical signs.  
Lactate 5 to 10 mmol/L without symptoms: monitor closely.  
Lactate 5 to 10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia,  
diabetic ketoacidosis, thyrotoxicosis, lymphoma).  
Lactate greater than or equal to 10 mmol/L: STOP all therapy (80 % mortality in case studies).  
Initials_____________  
November 2021  
Page 4 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Patients Co-infected with HIV and HBV  
It is recommended that all patients with HIV be tested for the presence of chronic HBV before initiating anti-  
retroviral therapy. HETRIPCO is not indicated for the treatment of chronic HBV infection and the safety and  
efficacy of HETRIPCO have not been established in patients co-infected with HBV and HIV. Severe acute  
exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have  
discontinued emtricitabine or tenofovir DF. In some of these patients treated with emtricitabine, the  
exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function  
should be monitored closely with both clinical and laboratory follow-up for at least several months in patients  
who are co-infected with HIV and HBV and discontinue HETRIPCO. If appropriate, initiation of anti-hepatitis  
B therapy may be warranted.  
Co-administration with Related Medicines  
Related medicines not for co-administration with HETRIPCO include emtricitabine, tenofovir DF,  
emtricitabine / tenofovir DF and efavirenz, which contain the same active components as HETRIPCO. Due to  
similarities between emtricitabine and lamivudine, HETRIPCO should not be co-administered with medicines  
containing lamivudine, including lamivudine / zidovudine, lamivudine, abacavir sulphate / lamivudine or  
abacavir sulphate / lamivudine / zidovudine.  
Medicine Interactions (see Section 4.5)  
Concomitant use of HETRIPCO and St. John's Wort (Hypericum perforatum) or St. John's Wort-containing  
products is not recommended. Co-administration of NNRTIs, including efavirenz, with St. John's Wort is  
expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of efavirenz  
and lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.  
Co-administration of HETRIPCO and didanosine is not recommended since exposure to didanosine is  
Initials_____________  
November 2021  
Page 5 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
significantly increased following co-administration with tenofovir disoproxil that may increase the risk of  
didanosine-related adverse reactions (see Section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes  
fatal have been reported.  
Co-administration of HETRIPCO and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not  
recommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decrease  
following co-administration with efavirenz leading to reduced therapeutic effect of sofosbuvir/velpatasvir or  
sofosbuvir/velpatasvir/voxilaprevir (see Section 4.5).  
Psychiatric Symptoms  
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz (see Section  
4.8).  
Nervous System Symptoms  
Patients receiving HETRIPCO should be alerted to the potential for additive central nervous system effects  
when HETRIPCO is used concomitantly with alcohol or psycho-active medicines (see Section 4.5).  
Patients who experience central nervous system symptoms such as dizziness, impaired concentration,  
and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery (see  
Section 4.7).  
Neurotoxicity  
Efavirenz, as contained in HETRIPCO may cause long-term neuropsychiatric effects. Severe reversible  
ataxia often with signs of encephalopathy, associated with supra-therapeutic efavirenz concentrations were  
reported in underweight women (less than 40 kg) who were probably slow metabolisers. Cases of efavirenz-  
induced hyper-somnolence resulting in coma and death and brain histology demonstrated by vacuolar  
axonopathy were reported. Lower doses of efavirenz and therapeutic drug monitoring should be considered  
Initials_____________  
November 2021  
Page 6 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
in patients with body weight of less than 40 kg and patients presenting with severe and prolonged  
neuropsychiatric manifestations. As a dose reduction of efavirenz, only, is not possible with HETRIPCO,  
such patients should be treated with separate formulations of the active ingredients.  
Liver failure  
There is some evidence that efavirenz is associated with three clinical pathological patterns of drug induced  
liver failure in HIV positive patients of which the sub massive necrosis histological pattern seems to be  
associated with a high morbidity/mortality risk and may present many months after therapy has been initiated  
or even stopped. Risk factors include younger age, CD4+ counts ≥ 350 cells/μL and female gender.  
Patients on HETRIPCO or efavirenz containing antiretroviral treatment (ART) should be regularly monitored  
for jaundice (including a laboratory bilirubin and liver enzymes) and bleeding tendencies.  
Early detection and treatment of the liver failure and the immediate discontinuation of HETRIPCO or  
efavirenz containing medicines should be stressed. Patients who discontinued treatment with HETRIPCO  
should be followed up for symptoms/signs of liver failure for up to 12 months.  
HETRIPCO is not recommended in patients with moderate hepatic impairment because there are insufficient  
data to determine whether dose adjustments are required. HETRIPCO is contraindicated in patients with  
severe hepatic impairment (see Section 4.3).  
The safety and efficacy of HETRIPCO in patients with both HIV and hepatitis 8 virus infection have not been  
established.  
Renal Impairment (see Section 4.2)  
Emtricitabine and tenofovir are principally eliminated by the kidney, however efavirenz is not. Since  
Initials_____________  
November 2021  
Page 7 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
HETRIPCO is a combination product and the dose of the individual components cannot be altered, patients  
with creatinine clearance less than 50 ml/min should not receive HETRIPCO.  
140- age x mass(kg)  
CrCl (ml/min) =  
72 x serum creatinine (mg/dl)  
* For females multiply the GFR by 0,85  
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with  
severe hypophosphataemia), has been reported in association with the use of tenofovir DF (see Section  
4.8).  
It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as  
clinically appropriate during therapy with HETRIPCO. Routine monitoring of calculated creatinine clearance  
and serum phosphorus should be performed in patients at risk for renal impairment.  
HETRIPCO should be avoided with concurrent or recent use of a nephrotoxic medicine.  
Reproductive Risk Potential  
Efavirenz may cause foetal harm when administered during the first trimester to a pregnant woman.  
Pregnancy should be avoided in women receiving HETRIPCO. Barrier contraception should always be used  
in combination with other methods of contraception (e.g. oral or other hormonal contraceptives). Women of  
childbearing potential should undergo pregnancy testing before initiation of HETRIPCO. If this medicine is  
used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this medicine,  
the patient should be apprised of the potential harm to the foetus (see Section 4.6).  
Paediatric Use  
HETRIPCO is not recommended for patients < 18 years of age as safety and efficacy have not been  
Initials_____________  
November 2021  
Page 8 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
established.  
Geriatric Use  
Dose selection for the elderly patients should be cautious, due to the greater frequency of decreased  
hepatic, renal or cardiac function and of concomitant disease or other medicine therapy (see Section 4.2).  
Skin Rash  
Mild to moderate rash has been reported in patients treated with efavirenz and usually resolves with  
continued therapy. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten  
the resolution of rash. HETRIPCO can be reinitiated in patients interrupting therapy because of rash.  
HETRIPCO should be discontinued in patients developing severe rash associated with blistering,  
desquamation, mucosal involvement or fever (see Section 4.8).  
Liver Enzymes  
In patients with known or suspected history of hepatitis B or C infection and in patients treated with other  
medications associated with liver toxicity, monitoring of liver enzymes is recommended (see Section 4.4).  
Patients Co-infected with HIV and HBV). In patients with persistent elevations of serum transaminases to  
greater than five times the upper limit of the normal range, the benefit of continued therapy with HETRIPCO  
needs to be weighed against the unknown risks of significant liver toxicity (see Section 4.8).  
Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited clinical experience  
in patients with hepatic impairment, caution should be exercised in administering HETRIPCO to these  
patients.  
Bone Effects  
Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with  
Initials_____________  
November 2021  
Page 9 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
the use of tenofovir (see Section 4.8).  
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.  
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.  
Convulsions  
Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical  
history of seizures. Caution must be taken in any patient with a history of seizures.  
Patients who are receiving concomitant anticonvulsant medications primarily metabolised by the liver, such  
as phenytoin and phenobarbital, may require periodic monitoring of plasma levels (see Section 4.5).  
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.  
Initials_____________  
November 2021  
Page 10 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
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 Grave’s 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.  
Opportunistic infections  
Patients receiving HETRIPCO 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 experiences 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 HETRIPCO, does not prevent the risk  
of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions  
should continue to be employed.  
Initials_____________  
November 2021  
Page 11 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
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. The main adverse events reported are  
haematological  
disorders  
(anaemia,  
neutropenia)  
and  
metabolic  
disorders  
(hyperlactataemia,  
hyperlipidaemia). These events are often transitory. Some late-onset neurological disorders have been  
reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or  
permanent is not known. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV  
negative children, should have clinical and laboratory follow-up and should be fully investigated for possible  
mitochondrial dysfunction in case of relevant sign and symptoms (see Section 4.8).  
QTc Prolongation  
QTc prolongation has been observed with the use of efavirenz (see Sections 4.5 and 5.2). For patients at  
increased risk of Torsade de Pointes or who are receiving drugs with a known risk for Torsade de Pointes,  
consider alternatives to HETRIPCO.  
Weight and metabolic parameters  
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such  
changes may in part be linked to disease control and life-style. For lipids, there is in some cases evidence for  
a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment.  
For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid  
disorders should be managed as clinically appropriate.  
Oral contraceptives  
The potential interaction of efavirenz with oral contraceptives such as ethinyl estradiol has not been fully  
characterized. A reliable method of barrier contraception should be used in addition to oral contraceptives  
Initials_____________  
November 2021  
Page 12 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
(see Section 4.5).  
4.5 Interaction with other medicines and other forms of interaction  
Efavirenz: Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of  
CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. In vitro studies  
have demonstrated that efavirenz inhibits 2C9, 2C19 and 3A4 isozymes in the range of observed efavirenz  
plasma concentrations. Co-administration of efavirenz with medicines primarily metabolised by these  
isozymes may result in altered plasma concentrations of the co-administered medicine. Therefore,  
appropriate dose adjustments may be necessary for these medicines.  
Medicines which induce CYP3A4 activity (e.g. phenobarbital, rifampicin, rifabutin) would be expected to  
increase the clearance of efavirenz resulting in lowered plasma concentrations.  
Efavirenz exposure may be increased when given with grapefruit juice which inhibits CYP3A4 or CYP2B6  
activity.  
Emtricitabine and tenofovir disoproxil fumarate: Since emtricitabine and tenofovir are primarily  
eliminated by the kidneys, co-administration of HETRIPCO with medicines that reduce renal function 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, acyclovir, adefovir  
dipivoxil, cidofovir, ganciclovir, valaciclovir and valganciclovir.  
Co-administration of tenofovir 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 (for didanosine dosing  
adjustment recommendations, see Table 2). Suppression of CD4 cell counts has been observed in patients  
Initials_____________  
November 2021  
Page 13 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
receiving tenofovir DF with didanosine at a dose of 400 mg daily.  
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of  
this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse  
events, including renal disorders. Patients receiving either atazanavir or lopinavir/ritonavir with tenofovir DF  
should be monitored for tenofovir-associated adverse events. HETRIPCO should be discontinued in patients  
who develop tenofovir-associated adverse events (for atazanavir dosing adjustment recommendations, see  
Table 2).  
Other important medicine interaction information for HETRIPCO is summarised Tables 1 and 2. The  
medicine interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF  
as individual medicines or are potential medicine interactions; no medicine interaction studies have been  
conducted using HETRIPCO. The tables include potentially significant interactions, but are not all inclusive.  
Table 1  
Medicines that are Contraindicated or not recommended for use with HETRIPCO (see Section 4.3)  
Medicine  
Clinical Comment / Contraindicated  
Efavirenz significantly decreases voriconazole plasma concentrations  
and co-administration may decrease the therapeutic effectiveness of  
voriconazole. Voriconazole significantly increases efavirenz plasma  
concentrations, which may increase the risk of efavirenz-associated  
side effects.  
Antifungal: voriconazole  
Potential for serious and/or life-threatening reactions such as cardiac  
dysrhythmias.  
Antihistamine: astemizole  
Anti-migraine: ergot  
derivatives  
Potential for serious and/or life-threatening reactions such as acute  
ergot toxicity characterised by peripheral vasospasm and ischaemia  
of the extremities and other tissues.  
(dihydroergotamine,  
ergonovine, ergotamine)  
Anti-retrovirals: efavirenz,  
Not for use with HETRIPCO because the active ingredients,  
Initials_____________  
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Page 14 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
emtricitabine, tenofovir DF,  
lamivudine  
emtricitabine, tenofovir, emtricitabine/tenofovir and efavirenz are  
components of HETRIPCO. Lamivudine is similar to emtricitabine.  
Potential for serious and/or life-threatening reactions such as  
prolonged or increased sedation or respiratory depression.  
Potential for serious and/or life-threatening reactions such as cardiac  
dysrhythmias.  
Benzodiazepines:  
midazolam, triazolam  
Calcium channel blocker.  
bepridil  
Gl motility medicine:  
cisapride  
Potential for serious and/or life-threatening reactions such as cardiac  
dysrhythmias.  
Potential for serious and/or life-threatening reactions such as cardiac  
dysrhythmias.  
Neuroleptic: pimozide  
NOT RECOMMENDED: Expected to substantially decrease plasma  
levels of efavirenz; has not been studied in combination with  
efavirenz.  
St. John's Wort (Hypericum  
perforatum)  
Table 2  
Established and Other Potentially Significant Medicine Interactions:  
Alteration in Dose or Regimen May Be Recommended Based on Medicine Interaction Studies or  
Predicted Interaction  
1 This table is not all inclusive  
Concomitant Medicine  
Effect  
Clinical Comment  
Anti-retroviral medicines  
↓amprenavir  
concentration  
↓fosamprenavir  
concentration  
Efavirenz has the potential to decrease serum  
concentrations of amprenavir  
Protease inhibitor: Amprenavir  
Protease inhibitor:  
Fosamprenavir (unboosted): Appropriate doses of  
fosamprenavir and HETRIPCO with respect to  
safety and efficacy have not been established.  
Fosamprenavir/ritonavir: An additional 100 mg/day  
(300 mg total) of ritonavir is recommended when  
Fosamprenavir calcium  
HETRIPCO  
is  
administered  
with  
fosamprenavir/ritonavir daily. No change in the  
ritonavir dose is required when HETRIPCO is  
administered with fosamprenavir plus ritonavir twice  
Initials_____________  
November 2021  
Page 15 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
daily.  
Protease inhibitor: Atazanavir  
↓atazanavir  
concentration  
↑tenofovir  
Plasma  
concentrations  
of  
atazanavir  
were  
decreased by both efavirenz and tenofovir.  
Sufficient data are not available to make a dosing  
concentration  
recommendation  
for  
atazanavir  
or  
atazanavir/ritonavir with HETRIPCO. Therefore, co-  
administration of HETRIPCO and atazanavir is not  
recommended  
decreased atazanavir concentrations.  
The optimal dose of indinavir, when given in  
combination with efavirenz, is not known.  
due  
to  
concerns  
regarding  
Protease inhibitor: Indinavir  
↓indinavir  
concentration  
Increasing the indinavir dose to 1 000 mg every 8  
hours does not compensate for the increased  
indinavir metabolism due to efavirenz.  
Protease inhibitor:  
lopinavir/ritonavir  
↓lopinavir  
A dose increase of lopinavir/ritonavir to 600/150 mg  
(3 tablets) twice daily may be considered when used  
in combination with efavirenz in treatment-  
experienced patients where decreased susceptibility  
to lopinavir is clinically suspected (by treatment  
history of laboratory evidence). Patients should be  
monitored for tenofovir-associated adverse events.  
HETRIPCO should be discontinued in patients who  
develop tenofovir-associated adverse events.  
When ritonavir 500 mg every 12 hours was co-  
administered with efavirenz 600 mg once daily, the  
combination was associated with a higher frequency  
of adverse clinical experiences (e.g. dizziness,  
nausea, paraesthesia) and laboratory abnormalities  
(elevated liver enzymes). Monitoring of liver  
enzymes is recommended when HETRIPCO is  
used in combination with ritonavir.  
concentration  
↑tenofovir  
concentration  
Protease inhibitor: Ritonavir  
↑ritonavir  
concentration  
↑efavirenz  
concentration  
Protease inhibitor: Saquinavir  
NRTI:  
↓saquinavir  
concentration  
↑didanosine  
Should not be used as sole protease inhibitor in  
combination with HETRIPCO.  
Higher didanosine concentrations could potentiate  
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Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Didanosine  
concentration  
didanosine-associated adverse events, including  
pancreatitis and neuropathy. In adults weighing  
more than 60 kg, the didanosine dose should be  
reduced to 250 mg if co-administered with  
HETRIPCO. Data are not available to recommend a  
dose adjustment of didanosine for patients weighing  
less than 60 kg. When co-administered, HETRIPCO  
and didanosine may be taken under fasted  
conditions or with a light meal (less than 400 kcal,  
20 % fat). Co-administration of didanosine buffered  
formulation with HETRIPCO should be under fasted  
conditions. Co-administration of HETRIPCO and  
didanosine should be taken with caution and  
patients receiving this combination should be  
monitored  
closely  
for  
didanosine-associated  
adverse events. For additional information, please  
consult the didanosine professional information.  
Other medicines  
Anticoagulant: Warfarin  
↑or↓ warfarin  
Plasma concentrations and effects potentially  
increased or decreased by efavirenz.  
concentration  
Anticonvulsants:  
Carbamazepine  
↓ carbamazepine There are insufficient data to make a dose  
concentration  
↓efavirenz  
recommendation for HETRIPCO.  
Alternative anticonvulsant treatment should be used.  
concentration  
↓anticonvulsant  
concentration  
↓efavirenz  
Phenytoin, phenobarbitone  
Potential for reduction in anticonvulsant and/or  
efavirenz plasma levels; periodic monitoring of  
anticonvulsant plasma levels should be conducted.  
concentration  
↓sertraline  
Antidepressant: Sertraline  
Antifungals: Itraconazole  
Increases in sertraline dose should be guided by  
clinical response.  
concentration  
↓itraconazole  
concentration  
Since no dose recommendation for itraconazole can  
be made, alternative antifungal treatment should be  
considered.  
↓hydroxy-  
Initials_____________  
November 2021  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Ketoconazole  
itraconazole  
concentration  
↓ketoconazole  
concentration  
↓clarithromycin  
concentration  
↑14-OH  
Medicine interaction studies with HETRIPCO and  
ketoconazole have not been conducted. Efavirenz  
has the potential to decrease plasma concentrations  
of ketoconazole.  
Anti-infective: Clarithromycin  
Clinical  
significance  
unknown.  
In  
uninfected  
volunteers, 46 % developed rash while receiving  
efavirenz and clarithromycin. No dose adjustment of  
HETRIPCO is recommended when given with  
clarithromycin. Alternatives to clarithromycin, such  
as azithromycin, should be considered. Other  
macrolide antibiotics, such as erythromycin, have  
not been studied in combination with HETRIPCO.  
Increase daily dose of rifabutin by 50 %. Consider  
doubling the rifabutin dose in regimens where  
rifabutin is given 2 or 3 times a week.  
metabolite  
concentration  
Antimycobacterial: Rifabutin  
Antimycobacterial: Rifampicin  
↓rifabutin  
concentration  
↓efavirenz  
Clinical  
significance  
of  
reduced  
efavirenz  
concentration  
concentration is unknown. Dosing recommendations  
for concomitant use of HETRIPCO and rifampicin  
have not been established.  
Calcium channel blockers:  
Diltiazem  
↓diltiazem  
Diltiazem dose adjustments should be guided by  
clinical response (refer to the complete professional  
information for diltiazem). No dose adjustment of  
HETRIPCO is necessary when administered with  
diltiazem.  
concentration  
↓desacetyl  
diltiazem  
concentration  
Others  
↓N-monodes-  
methyl diltiazem  
concentration  
No data are available on the potential interactions of  
efavirenz with other calcium channel blockers that  
are substrates of the CYP3A4 enzyme. The  
(e.g. felodipine, nicardipine,  
nifedipine, verapamil)  
↓calcium channel potential  
blocker  
exists  
for  
reduction  
in  
plasma  
concentrations of the calcium channel blocker. Dose  
adjustments should be guided by clinical response  
(refer to the complete professional information for  
the calcium channel blocker).  
HMG-CoA reductase inhibitors: ↓atorvastatin  
Plasma concentrations of atorvastatin, pravastatin  
Initials_____________  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Atorvastatin Pravastatin  
Simvastatin  
concentration  
↓pravastatin  
concentration  
↓simvastatin  
concentration  
↓methadone  
concentration  
and simvastatin decreased with efavirenz. Consult  
the complete professional information for the HMG-  
CoA  
reductase  
inhibitor  
for  
guidance  
on  
individualising the dose.  
Narcotic analgesic:  
Methadone  
Co-administration of efavirenz in HIV-infected  
individuals with a history of injection medicine use  
resulted in decreased plasma levels of methadone  
and signs of opiate withdrawal. Methadone dose  
was increased by a mean of 22 % to alleviate  
withdrawal symptoms. Patients should be monitored  
for signs of withdrawal and their methadone dose  
increased as required to alleviate withdrawal  
symptoms.  
Oral contraceptive: Ethinyl  
oestradiol  
↑ethinyl oestradiol Clinical significance unknown. Because the potential  
concentration  
interaction of efavirenz with oral contraceptives has  
not been fully characterised, a reliable method of  
barrier contraception should be used in addition to  
oral contraceptives.  
Efavirenz Assay Interference  
Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine  
cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the  
Microgenics Cedia DAU Multi-Level THC assay was used for screening. Negative results were obtained  
when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. For  
more information, please consult the efavirenz professional information.  
Other Interactions  
Efavirenz  
Medicine interaction studies were performed with efavirenz and other medicines likely to be co-administered  
or medicines commonly used as probes for pharmacokinetic interaction. There was no clinically significant  
Initials_____________  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
interaction observed between efavirenz and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam,  
cetirizine or paroxetine. Single doses of famotidine or an aluminium and magnesium antacid with  
simethicone had no effects on efavirenz exposures.  
Emtricitabine and tenofovir disoproxil fumarate  
No clinically significant medicine interactions have been observed between emtricitabine and famciclovir,  
indinavir, stavudine, tenofovir and zidovudine. Similarly, no clinically significant medicine interactions have  
been observed between tenofovir and abacavir, adefovir, dipivoxil, efavirenz, emtricitabine, indinavir,  
lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin and saquinavir/ritonavir in  
studies conducted in healthy volunteers.  
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy,  
oral contraceptives or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those  
observed in previous studies, indicating a lack of clinically significant medicine interactions between these  
medicines and tenofovir.  
4.6 Fertility, pregnancy and lactation  
Women of childbearing potential / Contraception in males and females  
Pregnancy should be avoided in women receiving HETRIPCO. Women of childbearing potential should  
undergo pregnancy testing before initiation of HETRIPCO. Barrier contraception should always be used  
in combination with other methods of contraception (for example, oral or other hormonal contraceptives)  
while on therapy with HETRIPCO. Because of the long half-life of efavirenz, the use of adequate  
contraceptive measures for 12 weeks after discontinuation of HETRIPCO is recommended (see Section  
5.2).  
Pregnancy  
HETRIPCO should not be used in pregnancy (see Section 4.3).  
Initials_____________  
November 2021  
Page 20 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Efavirenz is teratogenic and may cause foetal harm when administered during the first trimester of  
pregnancy. There have been reports of congenital abnormalities including neural tube defects and  
meningomeroceal in babies exposed in utero to efavirenz during the first trimester of pregnancy.  
If a patient becomes pregnant while taking HETRIPCO the patient (and partner) should be counselled  
and informed about the potential harm to the foetus. The possibility of termination of pregnancy should be  
considered and discussed with both patients if there is already evidence of severe harm to the foetus. If  
termination is unavoidable the patient should be treated with an alternative medicine, known to be safe or  
safer for use in pregnancy. If no safe or safer alternative is available, cannot be tolerated, has failed or is  
contraindicated, both partners should be counselled and written consent preferable to both partners be  
obtained to continue treatment with HETRIPCO.  
If a patient is to be treated with HETRIPCO, pregnancy should be excluded 24 hours prior to initiation of  
treatment.  
Breastfeeding  
It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal  
transmission of HIV. Because of both the potential for HIV transmission and the potential for serious  
adverse reactions in breastfed infants, mothers should be instructed not to breastfeed if they are  
receiving HETRIPCO.  
Fertility  
Human data on the effect of HETRIPCO on fertility are not available.  
4.7 Effects on ability to drive and use machines  
Initials_____________  
November 2021  
Page 21 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Dizziness, impaired concentration and drowsiness have been reported during treatment with the individual  
components of HETRIPCO. If the patient experiences any of these symptoms while taking HETRIPCO,  
he/she should be advised not to drive or use any tools or machines (see Section 4.8).  
4.8 Undesirable effects  
a. Summary of safety profile  
For additional safety information about efavirenz, emtricitabine or tenofovir in combination with other anti-  
retroviral medicines, consult the professional informations for these products.  
Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme, neuropsychiatric  
adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures),  
severe hepatic events, pancreatitis and lactic acidosis (sometimes fatal) have been reported.  
Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including  
Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have  
also been reported. Monitoring of renal function is recommended for patients receiving HETRIPCO (see  
Section 4.4).  
Discontinuation of HETRIPCO therapy in patients co-infected with HIV and HBV may be associated with  
severe acute exacerbations of hepatitis (see Section 4.4).  
The administration of HETRIPCO with food may increase efavirenz exposure and may lead to an increase in  
the frequency of adverse reactions (see Sections 4.4 and 5.2).  
b. Listing of adverse reactions  
Initials_____________  
November 2021  
Page 22 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
EFAVIRENZ  
Infections and Infestations  
Frequent:  
Folliculitis  
Immune system disorders  
Less frequent:  
Allergic reactions  
Immune reconstitution syndrome  
Frequency unknown:  
Metabolism and nutrition disorders  
Less frequent:  
Anorexia, hypercholesterolaemia, hypertriglyceridaemia  
Frequency unknown:  
Redistribution/accumulation of body fat (see Section 4.4), alcohol intolerance  
increased appetite  
Psychiatric disorders  
Frequent:  
Insomnia  
Less frequent:  
Agitation, stupor, depression, anxiety, hallucination, euphoria, abnormal  
thinking, apathy, aggressive reactions, emotional lability, mania, psychosis,  
suicide  
Frequency unknown:  
Paranoia, neurosis, delusions, aggravated depression  
Nervous system disorders  
Frequent:  
Dizziness, headache, drowsiness  
Less frequent:  
Taste perversion, abnormal dreams, confusion, impaired concentration,  
somnolence, amnesia, migraine headaches, neuralgia, peripheral neuropathy,  
speech disorder, abnormal co-ordination, ataxia, convulsions, hypoaesthesia,  
paraesthesia, neuropathy, tremor  
Initials_____________  
November 2021  
Page 23 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Eye disorders  
Frequency unknown:  
Abnormal vision  
Ear and labyrinth disorders  
Frequency unknown:  
Tinnitus  
Cardiac disorders  
Frequency unknown:  
Palpitations  
Vascular disorders  
Less frequent:  
Flushing or hot flushes, syncope  
Respiratory, thoracic and mediastinal disorders  
Frequency unknown:  
Dyspnoea, asthma, sinusitis, upper respiratory tract infections  
Gastrointestinal disorders  
Frequent:  
Nausea  
Less frequent:  
Frequency unknown:  
Dyspepsia, abdominal pain, abdominal coordination, vomiting, diarrhoea  
Constipation, malabsorption, gastritis, gastroenteritis, gastro-oesophageal reflux  
Hepato-biliary disorders  
Less frequent:  
Hepatitis  
Hepatic failure  
Frequency unknown:  
Initials_____________  
November 2021  
Page 24 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Skin and subcutaneous tissue disorders  
Frequent:  
Rash pruritus, increased sweating, alopecia, eczema, skin exfoliation, urticaria,  
flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome  
Acne, seborrhoea, nail disorders, skin discolouration  
Less frequent:  
Musculoskeletal, connective tissue and bone disorders  
Less frequent:  
Arthralgia, myalgia  
Myopathy  
Frequency unknown:  
Reproductive system and breast disorders  
Frequency unknown:  
Gynaecomastia, impotence, decreased libido, increased libido  
General disorders and administrative site conditions  
Frequent:  
Fatigue  
Less frequent:  
Frequency unknown:  
Malaise  
Pain, influenza-like symptoms, asthenia  
Investigations  
Frequent:  
Weight increase and weight decrease  
Increased hepatic enzyme  
Frequency unknown:  
EMTRICITABINE  
Blood and the lymphatic system disorders  
Frequent:  
Neutropenia  
Less frequent:  
Anaemia, hyperbilirubinaemia, hepatitis  
Initials_____________  
November 2021  
Page 25 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Immune system disorders  
Frequent:  
Allergic reaction  
Angioedema  
Frequency unknown:  
Metabolism and nutrition disorders  
Frequent:  
Hypertriglyceridaemia, hyperglycaemia  
Frequency unknown:  
Accumulation and redistribution of body fat, including breast enlargement,  
central obesity, cushingoid appearance, dorsocervical fat enlargement (buffalo  
hump), facial wasting and peripheral wasting  
Psychiatric disorders  
Frequent:  
Insomnia  
Nervous system disorders  
Frequent:  
Abnormal dreams, dizziness, headache  
Gastrointestinal disorders  
Frequent:  
Nausea, diarrhoea  
Abdominal pain, dyspepsia, vomiting  
Less frequent:  
Skin and subcutaneous tissue disorders  
Frequent:  
Skin discolouration (increased pigmentation)  
Vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria  
Less frequent:  
Initials_____________  
November 2021  
Page 26 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
General disorders and administrative site conditions  
Less frequent:  
Asthenia, pain  
Investigations  
Frequent:  
Blood creatine phosphokinase increased  
Less frequent:  
Increased serum amylase concentrations including elevated pancreatic  
amylase, elevated serum lipase  
TENOFOVIR DISOPROXIL FUMARATE  
Infections and Infestations  
Frequency unknown:  
Pneumonia  
Blood and the lymphatic system disorders  
Frequency unknown: Neutropenia  
Immune system disorders  
Frequency unknown:  
Allergic reaction, angioedema, immune reconstitution syndrome  
Metabolism and nutrition disorders  
Frequent  
Hypophosphataemia  
Less frequent:  
Including fatal cases, usually associated with severe hepatomegaly and  
steatosis, anorexia, pancreatitis  
Frequency unknown:  
Accumulation and redistribution of body fat, including breast enlargement,  
central obesity, cushingoid appearance, dorsocervical fat enlargement (buffalo  
hump), facial wasting, and, peripheral wasting, hypertriglyceridaemia,  
Initials_____________  
November 2021  
Page 27 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
hyperglycaemia, hypokalaemia, Lactic acidosis  
Psychiatric disorders  
Frequent:  
Anxiety, insomnia, depression  
Nervous system disorders  
Frequent:  
Dizziness  
Headache, peripheral neuropathy, convulsions  
Frequency unknown:  
Gastrointestinal disorders  
Frequent:  
Nausea, vomiting, diarrhoea  
Less frequent:  
Frequency unknown:  
Abdominal pain, flatulence  
Dyspepsia  
Hepato-biliary disorders  
Less frequent:  
Hepatotoxicity  
Hepatitis, hepatic steatosis  
Frequency unknown:  
Skin and subcutaneous tissue disorders  
Frequent  
Skin rashes  
Sweating  
Frequency unknown:  
Musculoskeletal, connective tissue and bone disorders  
Frequency unknown: Myopathy, osteomalacia (both associated with proximal renal tubulopathy),  
muscular weakness, myalgia, arthralgia, osteonecrosis  
Initials_____________  
November 2021  
Page 28 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Renal and urinary disorders  
Frequency unknown:  
Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome,  
proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis,  
nephrogenic diabetes insipidus, polyuria, interstitial nephritis (including acute  
cases)  
General disorders and administrative site conditions  
Frequent:  
Asthenia, fatigue  
Frequency unknown:  
Fever, pain, back pain, chest pain  
Investigations  
Frequency unknown:  
Increased serum amylase concentrations, increased hepatic enzymes, weight  
decreased  
c) Description of selected adverse reactions  
Efavirenz: The most significant adverse events observed in patients treated with efavirenz are nervous  
system symptoms (see Section 4.4, nervous system symptoms), psychiatric symptoms (see Section 4.4,  
psychiatric symptoms) and rash (see Section 4.4, skin rash).  
Pancreatitis has been reported, although a causal relationship with efavirenz has not been established.  
Asymptomatic increases in serum amylase levels have been observed.  
Emtricitabine and tenofovir disoproxil fumarate: Adverse events that occurred in at least 5 % of patients  
receiving emtricitabine or tenofovir with other anti-retroviral medicines include anxiety, arthralgia, increased  
cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paraesthesia, peripheral neuropathy  
Initials_____________  
November 2021  
Page 29 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
(including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus,  
maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).  
Skin discolouration has been reported with higher frequency among emtricitabine treated patients. Skin  
discolouration, manifested by hyper-pigmentation on the palms and/or soles was generally mild and  
asymptomatic. The mechanism and clinical significance are unknown.  
d) Paediatric population  
Insufficient safety data are available for children below 18 years of age. HETRIPCO is not recommended in  
this population (see Section 4.2).  
e) Other special population  
Elderly: HETRIPCO has not been studied in patients over the age of 65. Elderly patients are more likely to  
have decreased hepatic or renal function, therefore caution should be exercised when treating elderly  
patients with HETRIPCO (see Section 4.2).  
Patients with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoring of  
renal function is recommended in any patient with mild renal impairment treated with HETRIPCO (see  
Sections 4.2, 4.4 and 5.2).  
HIV/HBV or HCV co-infected patients:  
The adverse reaction profile of efavirenz, emtricitabine and tenofovir disoproxil in patients co-infected with  
HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without co-infection.  
However, as would be expected in this patient population, elevations in AST and ALT occurred more  
frequently than in the general HIV infected population.  
Initials_____________  
November 2021  
Page 30 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infected with  
HBV, clinical and laboratory evidence of hepatitis may occur after discontinuation of treatment (see Section  
4.4).  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to  
report any suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”, found  
online under SAHPRA’s publications: https://www.sahpra.org.za/publications/Index/8 or to the Holder of  
certificate of registration through the mail: pvg.cdma@heterogroups.com .  
4.9 Overdose  
If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital  
signs and observation of the patient’s clinical status; standard supportive treatment should then be  
applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed  
efavirenz. Haemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information  
below), but is unlikely to significantly remove efavirenz from the blood.  
Efavirenz: Increased nervous system symptoms. Involuntary muscle contractions were reported.  
Emtricitabine: 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.  
Initials_____________  
November 2021  
Page 31 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Tenofovir disoproxil fumarate: Tenofovir is efficiently removed by haemodialysis with an extraction  
coefficient of approximately 54 %. Following a single 300 mg dose of tenofovir DF, a 4-hour  
haemodialysis session removed approximately 10 % of the administered tenofovir dose.  
PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties:  
A 20.2.8 Antiviral agents  
HETRIPCO is a fixed dose combination tablet containing efavirenz, emtricitabine and tenofovir disoproxil  
fumarate. Efavirenz is a non-nucleoside reverse transcriptase inhibitor; emtricitabine is a synthetic  
nucleoside analogue of cytidine, and tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside  
phosphonate (nucleotide) analogue of adenosine 5′-monophosphate.  
Mechanism of action:  
Efavirenz: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Efavirenz activity  
is mediated predominantly by non-competitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and  
human cellular DNA polymerases , β, , and are not inhibited by efavirenz.  
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  
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 , β, ε- and mitochondrial DNA polymerase .  
Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester  
analogue of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for  
Initials_____________  
November 2021  
Page 32 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
conversion to tenofovir and subsequent phosphorylations 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 , β and mitochondrial DNA polymerase .  
Antiviral Activity  
Efavirenz, emtricitabine and tenofovir disoproxil fumarate: Synergistic antiviral effects were observed in  
combination studies evaluating the antiviral activity in cell cultures of emtricitabine and efavirenz together,  
efavirenz and tenofovir together and emtricitabine and tenofovir together.  
Medicine Resistance  
Efavirenz, emtricitabine, and tenofovir disoproxil fumarate: HIV-1 isolates with reduced susceptibility to  
the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies.  
Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral  
RT.  
Cross-resistance  
Efavirenz, emtricitabine and tenofovir disoproxil fumarate: Cross-resistance has been recognised  
among NNRTIs. Cross resistance has also been recognised among certain NRTIs. The M184V/I and/or  
K65R substitutions selected in cell cultures by the combination of emtricitabine and tenofovir are also  
observed in some HIV-1 isolates from subjects failing treatment with tenofovir in 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 (see  
Section 4.4).  
5.2 Pharmacokinetic properties  
Initials_____________  
November 2021  
Page 33 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Efavirenz:  
Absorption  
In HIV-infected patients time-to-time peak plasma concentrations were approximately 3 to 5 hours and  
steady-state plasma concentrations are reached in 6 to 10 days. At a dose of efavirenz 600 mg once daily,  
steady-state Cmax was 12,9 ± 3,7 μM (mean ± SD), Cmin was 5,6 ± 3,2 μM, and AUC was 184 ± 73 μM•hr.  
Distribution  
Efavirenz is highly bound (approximately 99,5 to 99,75 %) to human plasma proteins, predominantly  
albumin.  
Biotransformation  
In vitro studies suggest CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism.  
Efavirenz has been shown to induce P450 enzymes, resulting in induction of its own metabolism. Efavirenz  
has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses.  
Elimination  
Following administration of 14C-labelled efavirenz, 14 to 34 % of the dose is recovered in the urine (mostly as  
metabolites) and 16 to 61 % is recovered in faeces (mostly as parent medicine)  
Emtricitabine:  
Absorption  
Emtricitabine is rapidly absorbed after oral administration with peak plasma concentrations occurring at 1 to  
2 hours post-dose. Following multiple dose oral administration of emtricitabine, the steady-state plasma  
emtricitabine Cmax was 1,8 ± 0,7 μg/ml (mean ± SD) and the AUC over a 24-hour dosing interval was 10,0 ±  
3,1 μg•hr/ml. The mean steady state plasma trough concentration at 24 hours post-dose was 0,09 μg/ml.  
The mean absolute bioavailability of emtricitabine was 93 %.  
Distribution  
In vitro binding of emtricitabine to human plasma proteins is less than 4 % and is independent of  
concentration over the range of 0,02 to 200 μg/ml.  
Initials_____________  
November 2021  
Page 34 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Biotransformation  
Following administration of radio-labelled emtricitabine, approximately 86 % is recovered in the urine and 13  
% is recovered as metabolites.  
Elimination  
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 with a renal  
clearance in adults with normal renal function of 213 ± 89 ml/min (mean ± SD). Following a single oral dose,  
the plasma emtricitabine half-life is approximately 10 hours.  
Tenofovir disoproxil fumarate:  
Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected patients in the fasted  
state, maximum serum concentrations (Cmax) were achieved in 1,0 ± 0,4 hours (mean ± SD) and Cmax and  
AUC values were 296 ± 90 ng/ml and 2 287 ± 685 ng•hr/ml, respectively. The oral bioavailability of tenofovir  
from tenofovir DF in fasted patients is approximately 25 %. In vitro binding of tenofovir to human plasma  
proteins is < 0,7 % and is independent of concentration over the range of 0,01 to 25 μg/ml. Approximately 70  
to 80 % of the intravenous dose of tenofovir is recovered as unchanged medicine in the urine. Tenofovir is  
eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in  
adults with normal renal function of 243 ± 33 ml/min (mean ± SD). Following a single oral dose, the terminal  
elimination half-life of tenofovir is approximately 17 hours.  
Effects of Food on Oral Absorption  
HETRIPCO has not been evaluated in the presence of food. Administration of efavirenz tablets with a high  
fat meal increased the mean AUC and Cmax of efavirenz by 28 % and 79 %, respectively, compared to  
administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and  
emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of  
Initials_____________  
November 2021  
Page 35 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
tenofovir by 35 % and 15 %, respectively, without affecting emtricitabine exposures (see Sections 4.9, 4.8  
and 4.4).  
Special populations  
Race  
Efavirenz: The pharmacokinetics of efavirenz in patients appear to be similar among the racial groups  
studied.  
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration  
of emtricitabine.  
Tenofovir disoproxil fumarate: There were insufficient numbers from racial and ethnic groups other than  
Caucasian to adequately determine potential pharmacokinetic differences among these populations following  
the administration of tenofovir DF.  
Gender  
Efavirenz, emtricitabine and tenofovir disoproxil fumarate:  
Efavirenz, emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.  
Paediatric and Geriatric Patients  
Pharmacokinetic studies have not been performed in paediatric patients (less than 18 years) and the elderly  
(more than 65 years)  
Patients with Impaired Renal Function  
Efavirenz: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency;  
however, less than 1 % of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on  
efavirenz should be minimal.  
Initials_____________  
November 2021  
Page 36 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
Emtricitabine and tenofovir disoproxil fumarate: The pharmacokinetics of emtricitabine and tenofovir are  
altered in patients with renal impairment. In patients with creatinine clearance less than 50 ml/min, Cmax and  
AUC10-∞ of emtricitabine and tenofovir were increased (see Sections 4.3 and 4.4).  
Patients with Hepatic Impairment  
Efavirenz: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic  
impairment (see Sections 4.4 and 4.8).  
Emtricitabine: The pharmacokinetics of emtricitabine have not been adequately studied in patients with  
hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of  
liver impairment should be limited.  
Tenofovir disoproxil fumarate: There were no substantial alterations in tenofovir pharmacokinetics in  
patients with hepatic impairment compared with unimpaired patients.  
5.3 Preclinical safety data  
Not Applicable  
Environmental Risk Assessment  
The environmental exposure of the active substance and metabolites are expected to be very limited. The  
use of efavirenz, emtricitabine and tenofovir disoproxil fumarate film coated tablets 600 mg / 200 mg / 300  
mg is not considered warranting any environmental concerns or requiring any special product labelling.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
Croscarmellose sodium  
microcrystalline cellulose  
sodium lauryl sulphate  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
•
•
hydroxypropyl cellulose  
magnesium stearate  
Film coating:  
Opadry II pink 85F94172 consists of polyvinyl alcohol-part hydrolysed, titanium dioxide, macrogol/PEG 3350,  
talc, iron oxide red, iron oxide black  
6.2 Incompatibilities  
Not applicable  
6.3 Shelf life  
36 months  
6.4 Special precautions for storage  
Store at or below 30 °C.  
Keep the container tightly closed.  
Protect from light and moisture.  
Keep the tablets in the HDPE bottle until required for use.  
Keep the HDPE bottle in the outer carton.  
6.5 Nature and contents of container  
•
•
28’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 28 film coated tablets.  
30’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 30 film coated tablets.  
Initials_____________  
November 2021  
Page 38 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
•
•
•
•
•
•
60’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 60 film coated tablets.  
84’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 84 film coated tablets.  
90’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 90 film coated tablets.  
120’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 120 film coated tablets.  
180’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 180 film coated tablets.  
500’s Count HDPE container: White opaque high density polyethylene (HDPE) container with a  
desiccant canister 2 g silica gel enclosed with a child-resistant plastic cap with a pulp liner,  
containing 500 film coated tablets.  
HDPE bottle is enclosed in an outer carton box.  
Not all pack sizes may be marketed.  
6.6 Special precautions for disposal and other handling  
No special requirements  
Initials_____________  
November 2021  
Page 39 of 40  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETRIPCO  
Dosage form and strength: Film coated tablets; 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir  
disoproxil fumarate (which is equivalent to 245 mg of tenofovir)  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus, Building 2,  
First Floor, 74 waterfall Drive,  
Midrand,2066  
8 REGISTRATION NUMBER(S)  
51/20.2.8/0200  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION  
05 May 2020  
10 DATE OF REVISION OF THE TEXT  
05 May 2020  
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