Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
Line  
1.  
Proposed Professional Information  
References  
SCHEDULING STATUS  
S4  
2.  
3.  
4.  
1 NAME OF THE MEDICINE  
5.  
HETERUAM 600/300 mg (Film coated tablets)  
6.  
7.  
BOX WARNING:  
8.  
Hypersensitivity: approximately 5 % of patients receiving HETERUAM  
develop a hypersensitivity reaction which in some cases is fatal (See  
section 4.8).  
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Risk Factors: Patients who carry the HLA-B*5701 allele are associated  
with a significant increased risk for experiencing a hypersensitive  
reaction. Avoiding abacavir in patients with this allele halved the  
incidence of clinical suspected abacavir hypersensitivity reactions. It is  
recommended that any HIV-infected patient without exposure to abacavir  
should be screened for carriage of the HLA-B*5701 allele. Use of  
abacavir in patients known to carry the HLA-B*5701 allele is not  
recommended. Screening is recommended prior to reinitiation of  
HETERUAM in patients of unknown HLA-B*5701 status, who have  
previously tolerated abacavir.  
In any patient treated with HETERUAM, the clinical diagnosis of  
suspected hypersensitivity reaction must remain the basis of clinical  
decision-making. Even in the absence of the HLA-B*5701 allele, it is  
important to permanently discontinue HETERUAM and not rechallenged  
with HETERUAM or other abacavir containing medicines if a  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
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hypersensitivity reaction cannot be ruled out on clinical grounds, due to  
the potential for a severe or even fatal reaction.  
Clinical Description: The symptoms of this hypersensitivity reaction can  
occur at any time during treatment with HETERUAM, but usually appear  
within the first six weeks of initiation of treatment. This is characterised  
by the presence of symptoms illustrative of multi-organ/body-system  
involvement. Most patients have fever and/or rash as part of the  
syndrome. Other symptoms include, gastrointestinal indicators (nausea,  
vomiting, diarrhoea, and abdominal pain), rash and fatigue or malaise,  
myalgia, arthralgia, oedema, paraesthesia, and respiratory signs and  
symptoms such as dyspnoea, sore throat, cough, and abnormal chest X-  
ray findings (predominantly infiltrates, which can be localised).The  
symptoms worsen with continued therapy and can be life-threatening.  
These symptoms usually resolve upon discontinuation of HETERUAM.  
Clinical Management: All patients developing signs or symptoms of  
hypersensitivity MUST contact their doctor immediately for advice.  
If a hypersensitivity reaction is diagnosed, HETERUAM MUST be  
discontinued immediately. HETERUAM, or any other medicine  
containing abacavir, MUST NEVER be restarted following a  
hypersensitivity reaction, as more severe symptoms will recur  
within hours and may include life-threatening hypotension and  
death.  
To avoid a delay in diagnosis and minimise the risk of a life-threatening  
hypersensitivity reaction, HETERUAM should be permanently  
discontinued if hypersensitivity cannot be ruled out, even when other  
diagnoses are possible (respiratory diseases, flu-like illness,  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
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gastroenteritis or reactions to other medications). HETERUAM, or any  
other medicine containing abacavir, should not be restarted even if  
recurrence of symptoms occurs following rechallenge with alternative  
medicines. An Alert Card with information for the patient about this  
hypersensitivity reaction is included in the HETERUAM pack.  
Special considerations following an interruption of HETERUAM  
therapy: If therapy with HETERUAM has been discontinued and  
restarting therapy is under consideration, the reason for discontinuation  
should be evaluated to ensure that the patient did not have symptoms of  
a hypersensitivity reaction. Patients who have stopped HETERUAM due  
to possible adverse reactions or illness should be advised to contact their  
doctor before restarting. If hypersensitivity cannot be ruled out  
HETERUAM or any other medicines containing abacavir should not  
be restarted.  
There have been less frequent reports of hypersensitivity reaction  
following re -introduction of abacavir, where the interruption was  
preceded by a single key symptom of hypersensitivity (rash, fever,  
malaise/fatigue, gastrointestinal symptoms or a respiratory  
symptom). If a decision is made to restart HETERUAM in these  
patients, this should be done only under direct medical  
supervision.  
Hypersensitivity reactions have been reported in patients who have  
restarted therapy, and who had no preceding symptoms of a  
hypersensitivity reaction. If a decision is made to restart HETERUAM,  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
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this must be done only if medical care can be accessed readily by the  
patient or others.  
It is recommended that any HIV-infected patient without exposure to  
abacavir should be screened for carriage of the HLA-B*5701 allele. Use  
of abacavir in patients known to carry the HLA-B*5701 allele is not  
recommended. Screening is recommended prior to reinitiation of  
HETERUAM in patients of unknown HLA-B*5701 status, who have  
previously tolerated abacavir.  
Essential patient information: Prescribers must ensure that patients  
are fully informed regarding the following information on the  
hypersensitivity reaction:  
•
•
•
•
•
Patients must be made aware of the possibility of a  
hypersensitivity reaction to abacavir that may result in a life-  
threatening reaction or death:  
Patients developing signs or symptoms possibly linked with a  
hypersensitivity reaction MUST CONTACT their doctor  
IMMEDIATELY.  
Patients who are hypersensitive to abacavir should be reminded  
that they must never take HETERUAM or any other medicines  
containing abacavir again.  
In order to avoid restarting HETERUAM, patients who have  
experienced a hypersensitivity reaction should be asked to  
return the remaining HETERUAM to the pharmacy.  
Patients who have stopped HETERUAM for any reason, and  
particularly due to possible adverse reactions or illness, must be  
advised to contact their doctor before restarting.  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
104.  
•
Each patient should be reminded to read the package insert  
included in the HETERUAM pack. They should be reminded of  
the importance of removing the Alert Card included in the pack,  
and keeping it with them at all times.  
105.  
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2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each capsule shaped film coated tablet contains abacavir sulphate  
equivalent to 600 mg abacavir and 300 mg lamivudine.  
HETERUAM tablets are sugar free.  
‘for full list of excipients, see section 6.1’  
3 PHARMACEUTICAL FORM  
Orange, capsule shaped, biconvex film coated tablets, debossed with ‘H’ on one  
side and ‘A1’ on other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
HETERUAM, in combination with other antiretroviral medicines, are indicated for  
the treatment of Human Immunodeficiency Virus (HIV) infection in adults and  
adolescents from 12 years of age.  
4.2 Posology and method of administration  
Posology  
Patients should be stabilised on the individual active ingredients, before being  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
129.  
switched over to HETERUAM. Therapy should be initiated by a medical  
practitioner experienced in the management of HIV infection. HETERUAM  
should not be administered to adults or adolescents who weigh less than 40 kg  
because it is a fixed-dose tablet that cannot be dose reduced.  
130.  
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The recommended oral dose of HETERUAM for adults is one tablet daily, in  
combination with other antiretroviral medicines.  
HETERUAM can be taken with or without food.  
Special population  
Elderly  
The pharmacokinetics of abacavir and lamivudine have not been studied in  
patients over 65 years of age. When treating elderly patients, consideration  
needs to be given to the greater frequency of decreased hepatic, renal and  
cardiac function, concomitant medicine or disease.  
Renal Impairment  
Renal impairment, whether disease- or age-related, affects lamivudine  
elimination. HETERUAM is a fixed dose tablet and should not be prescribed for  
patients requiring dosage adjustments (moderate to severe renal impairment)  
such as patients with a creatinine clearance below 50 ml/min.  
Hepatic impairment  
A dose reduction of abacavir is likely to be required for patients with mild  
hepatic impairment. As dose reduction is not possible with HETERUAM the  
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Product proprietary name: HETERUAM 600/300 mg  
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154.  
separate preparation of abacavir should be used when this is judged necessary.  
HETERUAM is contraindicated in patients with moderate and severe hepatic  
impairment (see section 5.2.).  
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177.  
178.  
Paediatric population  
Children  
HETERUAM is not recommended for treatment of children less than 12 years of  
age, as the necessary dose adjustment cannot be made.  
4.3 Contraindications  
Hypersensitivity to lamivudine or abacavir or any of the inactive ingredients of  
HETERUAM.  
HETERUAM is contraindicated in patients with previously demonstrated  
hypersensitivity to abacavir or to any other component of HETERUAM.  
NEVER restart HETERUAM or any other abacavir-containing product  
following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701  
status (See section 4.4).  
HETERUAM is contraindicated in patients with moderate to severe hepatic  
impairment. HETERUAM is contraindicated in patients with moderate to severe  
renal impairment (creatinine clearance < 50 ml/min).  
HETERUAM should not be administered to adults or adolescents who weigh less  
than 40 kg because it is a fixed-dose tablet that cannot be dose  
reduced.  
HETERUAM is not recommended to be used in combination with zalcitabine,  
since lamivudine may inhibit the intracellular phosphorylation of zalcitabine when  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
179.  
it is used concurrently.  
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4.4 Special warnings and precautions  
HYPERSENSITIVITY TO ABACAVIR HAS BEEN SHOWN IN  
APPROXIMATELY 5 % OF PATIENTS RECEIVING ABACAVIR, AS  
CONTAINED IN HETERUAM, WHICH IN SOME CASES PROVED  
FATAL. HYPERSENSITIVITY IS CHARACTERISED BY THE  
APPEARANCE OF SYMPTOMS INDICATING MULTIORGAN/BODY-  
SYSTEM INVOLVEMENT. PATIENTS WHO DEVELOP A  
HYPERSENSITIVITY REACTION MUST DISCONTINUE HETERUAM  
AND MUST NOT BE RECHALLENGED WITH HETERUAM OR ANY  
OTHER PRODUCT CONTAINING ABACAVIR (See section 4.8).  
Almost all patients developing hypersensitivity reactions will have fever  
and/or rash (usually maculopapular or urticarial) as part of the  
syndrome, however reactions have occurred without rash or fever.  
Symptoms can occur at any time while being treated with abacavir, but  
usually appear within the first six weeks of initiation of treatment  
(median time to onset is 11 days).  
The signs and symptoms of this hypersensitivity reaction are listed  
below. These have been identified either from clinical studies or post  
marketing surveillance:  
Infections and infestations: conjunctivitis  
Blood and the lymphatic system disorders: lymphopenia,  
lymphadenopathy  
Immune system disorders: Hypersensitivity  
Metabolism and nutrition disorders: oedema  
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Product proprietary name: HETERUAM 600/300 mg  
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205.  
Nervous system disorders: headache, paraesthesia  
Vascular disorders: hypotension  
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Respiratory, thoracic and mediastinal disorders: dyspnoea, cough, sore  
throat, adult respiratory distress syndrome, respiratory failure  
Gastrointestinal disorders: nausea, vomiting, diarrhoea, abdominal pain,  
mouth ulceration  
Hepato-biliary disorders: elevated liver function tests, hepatic failure  
Skin and subcutaneous tissue disorders: rash (usually maculopapular or  
urticaria)  
Musculoskeletal, connective tissue and bone disorders: myalgia, rarely  
myolysis, arthralgia, elevated creatine phosphokinase  
Renal and urinary disorders: elevated creatinine, renal failure  
General disorders and administrative site conditions: fever, fatigue,  
malaise.  
Some patients with hypersensitivity were initially thought to have  
respiratory disease (pneumonia, bronchitis, and pharyngitis), a flu-like  
illness, gastroenteritis or reactions to other medicines. This delay in  
diagnosis of hypersensitivity has resulted in abacavir being continued or  
re-introduced, leading to a more severe hypersensitivity reaction or  
death. Therefore, the diagnosis of hypersensitivity reaction should be  
carefully considered for patients presenting with symptoms of these  
diseases. If hypersensitivity reaction cannot be ruled out, HETERUAM,  
or any other medicine containing abacavir should not be restarted.  
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Product proprietary name: HETERUAM 600/300 mg  
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231.  
The symptoms related to this hypersensitivity reaction worsen with  
continued therapy, and usually resolve upon discontinuation of  
abacavir.  
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256.  
Restarting abacavir following a hypersensitivity reaction results in a  
prompt return of symptoms within hours. This recurrence of the  
hypersensitivity reaction may be more severe than on initial  
presentation,and may include life-threatening hypotension and death.  
Patients who develop this hypersensitivity reaction must discontinue  
HETERUAM and must never be rechallenged with HETERUAM, or any  
other medicine containing abacavir.  
There have been infrequent reports of hypersensitivity reactions  
following re-introduction of abacavir, where the interruption was  
preceded by a single key symptom of hypersensitivity (rash, fever,  
malaise/fatigue, gastrointestinal or a respiratory symptom).  
On very rare occasions hypersensitivity reactions have been reported in  
patients who have restarted therapy, and who had no preceding  
symptoms of a hypersensitivity reaction.  
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH  
STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED  
WITH USE OF LAMIVUDINE ALONE OR IN COMBINATION, IN THE  
TREATMENT OF HIV INFECTION. SEVERE EXECERBATIONS OF  
HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-  
INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1 AND HAVE  
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257.  
DISCONTINUED LAMIVUDINE; MONITOR HEPATIC FUNCTION  
UPON DISCONTINUATION OF THERAPY.  
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Lactic acidosis / hyperlactataemia:  
Use of HETERUAM 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/ℓ) and the serum bicarbonate and respond  
as follows:  
•
Lactate 2-5 mmol/ℓ with minimum symptoms: switch to medicines that  
are less likely to cause lactic acidosis.  
•
Lactate 5-10 mmol/ℓ with symptoms and/or with reduced standard  
bicarbonate: Stop NRTIs 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/ℓ: STOP all therapy (80 % mortality).  
The above lactate values may not be applicable to paediatric patients. Caution  
should be exercised when administering HETERUAM to patients with known risk  
factors for liver disease. Treatment with HETERUAM should be suspended in  
any patient who develops clinical or laboratory findings suggestive of lactic  
acidosis or hepatotoxicity.  
Mitochondrial dysfunction:  
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281.  
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:  
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305.  
Pancreatitis has been observed in some patients receiving HETERUAM.  
Pancreatitis must be considered whenever a patient develops abdominal pain,  
nausea, vomiting or elevated biochemical markers. Discontinue use of  
HETERUAM 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 lamivudine, an ingredient of HETERUAM, is increased due to decreased  
clearance. The dose of HETERUAM should therefore be adjusted (see section  
4.2).  
Liver disease:  
Use of HETERUAM can result in hepatomegaly due to non-alcoholic fatty liver  
disease (hepatic steatosis). The safety and efficacy of HETERUAM has not been  
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306.  
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:  
307.  
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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  
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 discontinue HETERUAM 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.  
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  
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331.  
redistribution. Patients with evidence of lipodystrophy should have a thorough  
cardiovascular risk assessment.  
332.  
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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.  
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  
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356.  
(cART). Patients should be advised to seek medical advice if they experience  
joint aches and pain, joint stiffness or difficulty in movement.  
Myocardial infarction:  
357.  
358.  
359.  
360.  
361.  
362.  
363.  
364.  
365.  
366.  
367.  
368.  
369.  
370.  
371.  
372.  
373.  
374.  
375.  
376.  
377.  
378.  
379.  
380.  
As a precaution the underlying risk of coronary heart disease should be  
considered when prescribing antiretroviral therapies, including abacavir, and  
action taken to minimise all modifiable risk factors (e.g. hypertension,  
hyperlipidaemia, diabetes mellitus and smoking).  
Opportunistic infections:  
Patients receiving HETERUAM 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 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  
HETERUAM, does not prevent the risk of transmission of HIV to others through  
sexual contact or blood contamination. Appropriate precautions should continue  
to be employed.  
4.5 Interaction with other medicines and other forms of interaction  
As HETERUAM contains abacavir and lamivudine, any interactions that have  
been identified with these medicines individually may occur with HETERUAM.  
Studies have shown that there are no clinically significant interactions between  
abacavir and lamivudine. Abacavir and lamivudine are not significantly  
metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
381.  
2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little  
potential for interactions with antiretroviral protease inhibitors, non-nucleosides  
and other medicines metabolised by major P450 enzymes.  
382.  
383.  
384.  
385.  
386.  
387.  
388.  
389.  
390.  
391.  
392.  
393.  
394.  
395.  
396.  
397.  
398.  
399.  
400.  
401.  
402.  
403.  
404.  
405.  
The likelihood of metabolic interactions with lamivudine is low due to limited  
metabolism and plasma protein binding, and almost complete renal clearance.  
Lamivudine is predominantly eliminated by active organic cationic secretion. The  
possibility of other medicines administered concurrently should be considered,  
particularly when the main route of elimination is renal.  
ABACAVIR interactions:  
Ethanol - The metabolism of abacavir is altered by concomitant ethanol resulting  
in an increase in AUC of abacavir of about 41 %. Given the safety profile of  
abacavir, these findings are not considered clinically significant. Abacavir has no  
effect on the metabolism of ethanol.  
Retinoids, i.e. isotretinoin - Possible interaction due to common pathway of  
elimination via alcohol dehydrogenase. Interaction is possible but has not been  
studied and there is insufficient data to recommend dosage adjustment.  
Methadone - In a pharmacokinetic study, co-administration of 600 mg abacavir  
twice daily with methadone showed a 35 % reduction in abacavir Cmax and a one-  
hour delay in Tmax, but AUC was unchanged. The changes in abacavir  
pharmacokinetics are not considered clinically relevant. In this study, abacavir  
increased the mean methadone systemic clearance by 22 %. This change is not  
considered clinically relevant for the majority of patients, however occasionally  
methadone dose re-titration may be required.  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
406.  
LAMIVUDINE interactions:  
407.  
408.  
409.  
410.  
411.  
412.  
413.  
414.  
415.  
416.  
417.  
418.  
419.  
420.  
421.  
422.  
423.  
424.  
425.  
426.  
427.  
428.  
429.  
430.  
Trimethoprim - Administration of trimethoprim/sulphamethoxazole 160 mg/800  
mg (co-trimoxazole) causes a 40 % increase in lamivudine exposure because of  
the trimethoprim component. However, unless the patient has renal impairment;  
no dosage adjustment of lamivudine is necessary (see section 4.2). Lamivudine  
has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole.  
The effect of co- administration of lamivudine with higher doses of co-trimoxazole  
used for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis has  
not been studied.  
Zalcitabine - Lamivudine may inhibit the intracellular phosphorylation of  
zalcitabine when the two medicines are used concurrently. HETERUAM is  
therefore, not recommended to be used in combination with zalcitabine.  
Co-administration of lamivudine with intravenous ganciclovir or  
foscarnet is not recommended.  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
The safe use of HETERUAM in human pregnancy has not been established.  
HETERUAM should not be used during pregnancy as teratogenicity has been  
observed.  
Breastfeeding  
It is recommended that where possible HIV infected women do not breastfeed  
their infants in order to avoid transmission of HIV. Lamivudine is excreted in  
human milk at similar concentrations to those found in serum. It is expected that  
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431.  
abacavir will also be secreted into human milk. It is therefore recommended that  
432.  
433.  
434.  
435.  
436.  
437.  
438.  
439.  
440.  
441.  
442.  
443.  
444.  
445.  
446.  
447.  
448.  
449.  
450.  
451.  
452.  
453.  
454.  
455.  
456.  
mothers do not breastfeed while receiving treatment with HETERUAM.  
4.7 Effects on ability to drive and use machines  
HETERUAM may cause side-effects such as dizziness or drowsiness, which  
may affect the ability to drive. Patients should therefore be advised not to drive or  
operate machinery until their individual susceptibility is known.  
4.8 Undesirable effects  
SYSTEM ORGAN  
CLASS  
FREQUENCY  
ADVERSE REACTION  
Infections and  
infestations  
Frequency  
unknown:  
Hepatitis B, exacerbation  
post treatment (see  
section 4.4).  
Blood and the  
lymphatic system  
disorders  
Frequent:  
Leukopenia, mainly  
neutropenia,  
thrombocytopenia and  
anaemia.  
Less frequent:  
Frequency  
unknown:  
Pure red cell aplasia.  
Hypersensitivity –  
angioedema,  
Immune system  
disorder  
anaphylaxis, urticaria  
Lipodystrophy  
Endocrine disorders  
Metabolism and  
Less frequent:  
Less frequent:  
Lactic acidosis (See  
section 4.4)  
nutrition disorders  
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457.  
Frequency  
unknown:  
Hyperglycaemia, insulin  
resistance,  
458.  
459.  
460.  
461.  
462.  
463.  
464.  
465.  
466.  
467.  
468.  
469.  
470.  
471.  
472.  
473.  
474.  
475.  
476.  
477.  
478.  
479.  
480.  
481.  
482.  
dyslipidaemia,  
hypertriglyceridaemia,  
hypercholesterolemia,  
hyperlactataemia.  
Depressive disorders  
Headache, fatigue,  
insomnia, peripheral  
neuropathy, dizziness  
and paraesthesia - more  
frequent in children.  
Peripheral neuropathy in  
adults  
Psychiatric disorders  
Nervous system  
disorders  
Less frequent:  
Frequent:  
Less frequent:  
Eye disorders  
Frequency  
unknown:  
Frequency  
unknown:  
Frequent:  
Conjunctivitis  
Vascular disorders  
Hypotension  
Respiratory, thoracic  
and mediastinal  
disorders  
Cough, nasal symptoms,  
wheezing (more  
frequently in children),  
dyspnoea  
Frequency  
unknown:  
Adult respiratory distress  
syndrome, respiratory  
failure  
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Dosage form and strength: Film coated tablet and 600/300 mg  
483.  
484.  
485.  
486.  
487.  
488.  
489.  
490.  
491.  
492.  
493.  
494.  
495.  
496.  
497.  
498.  
499.  
500.  
501.  
502.  
503.  
504.  
505.  
506.  
507.  
508.  
Gastrointestinal  
disorders  
Frequent:  
Pancreatitis, nausea,  
vomiting, abdominal  
pain/cramps, diarrhoea,  
decreased appetite,  
stomatitis / mouth  
ulceration.  
Less frequent:  
Frequent:  
Dyspepsia, elevations in  
serum amylase  
Hepato-biliary  
disorders:  
Transient elevations in  
liver enzymes (AST,  
ALT), splenomegaly,  
hepatitis, severe  
hepatomegaly with  
steatosis, some fatal  
cases in association with  
zidovudine.  
Skin and  
Frequent:  
Alopecia, maculopapular  
rash, erythema, pain,  
swelling, urticaria  
Hair loss, pruritus  
Arthralgia,  
subcutaneous tissue  
disorders  
Less frequent:  
Frequent:  
Musculoskeletal,  
connective tissue and  
bone disorders  
musculoskeletal pain  
Rhabdomyolysis  
Less frequent:  
General disorders and Less frequent:  
administration site  
Malaise and fever  
conditions  
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509.  
Investigations  
Rises in serum creatinine  
phosphokinase (s-CPK)  
and alanine  
510.  
511.  
512.  
513.  
514.  
515.  
aminotransferase (s-  
AAT) have been reported  
in patients with chronic  
hepatitis B.  
516.  
517.  
518.  
519.  
520.  
521.  
522.  
523.  
524.  
525.  
526.  
527.  
528.  
529.  
530.  
531.  
532.  
533.  
Post marketing surveillance data (see “hypersensitivity reaction” under section  
4.4).  
4.9 Overdose  
Symptoms: see section 4.8 and 4.4.  
In case of an overdose, the following information may prove useful:  
If overdose occurs the patient should be monitored for evidence of toxicity, and  
standard symptomatic and supportive treatment applied as necessary. Since  
lamivudine is dialysable, continuous haemodialysis could be used in the  
treatment of overdose, although this has not been studied. It is not known  
whether abacavir can be removed by peritoneal dialysis or haemodialysis.  
5 PHARMACOLOGICAL PROPERTIES  
PHARMACOLOGICAL CLASSIFICATION  
A 20.2.8 Antiviral agents.  
5.1 Pharmacodynamic properties  
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534.  
Both abacavir and lamivudine are nucleoside analogue reverse transcriptase  
inhibitors (NRTIs) and are selective inhibitors of HIV-1 and HIV-2. Both abacavir  
and lamivudine are metabolised sequentially by intracellular kinases to the  
respective triphosphate (TP) which are the active moieties. Lamivudine-TP  
and carbovir-TP (the active triphosphate form of abacavir) are substrates for and  
competitive inhibitors of HIV reverse transcriptase (RT). However, their main  
antiviral activity is through incorporation of the monophosphate form into the viral  
DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates  
show significantly less affinity for host cell DNA polymerases.  
535.  
536.  
537.  
538.  
539.  
540.  
541.  
542.  
543.  
544.  
545.  
546.  
547.  
548.  
549.  
550.  
551.  
552.  
553.  
554.  
555.  
556.  
557.  
558.  
Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting  
the replication of HIV in cell culture. Abacavir shows synergy in vitro in  
combination with amprenavir, nevirapine and zidovudine. It has been shown to  
be additive in combination with didanosine, zalcitabine, stavudine and  
lamivudine.  
Resistance:  
HIV-1 resistance to lamivudine involves the development of a M184V amino acid  
change close to the active site of the viral RT. This variant arises both in vitro and  
in HIV-1 infected patients treated with lamivudine-containing antiretroviral  
therapy. M184V mutants display greatly reduced susceptibility to lamivudine and  
show diminished viral replicative capacity in vitro. Studies in vitro indicate that  
zidovudine-resistant virus isolates can become zidovudine sensitive when they  
simultaneously acquire resistance to lamivudine. The clinical relevance of such  
findings remains, however, not well defined.  
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are  
associated with specific genotypic changes in the RT codon region (codons  
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559.  
M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively  
slowly in vitro and in vivo, requiring multiple mutations to reach an eight-fold  
increase in IC50 over wild-type virus, which may be a clinically relevant level.  
Isolates resistant to abacavir might also show reduced sensitivity to lamivudine,  
zalcitabine, tenofovir, emtricitabine and/or didanosine, but remain sensitive to  
zidovudine and stavudine.  
560.  
561.  
562.  
563.  
564.  
565.  
566.  
567.  
568.  
569.  
570.  
571.  
572.  
573.  
574.  
575.  
576.  
577.  
578.  
579.  
580.  
581.  
582.  
583.  
Cross-resistance between abacavir or lamivudine and antiretrovirals from other  
classes e.g. protease inhibitors (PI) or non-nucleoside reverse transcriptase  
inhibitors (NNRTI), is unlikely. Reduced susceptibility to abacavir has been  
demonstrated in clinical isolates of patients with uncontrolled viral replication,  
who have been pre-treated with and are resistant to other nucleoside inhibitors.  
Clinical isolates with three or more mutations associated with NRTIs are unlikely  
to be susceptible to abacavir. Cross-resistance conferred by the M184V RT is  
limited within the nucleoside inhibitor class of antiretroviral medicines.  
Zidovudine, stavudine, abacavir and tenofovir maintain their antiretroviral  
activities against lamivudine-resistant HIV-1 harbouring only the M184V  
mutation.  
5.2 Pharmacokinetic properties  
Absorption:  
Abacavir and lamivudine are well absorbed following oral administration. The  
absolute bioavailability of oral abacavir and lamivudine in adults is about 80 %  
and 80 to 87 % respectively. The mean time to maximal serum concentrations  
(Tmax) is about 1,5 hours and 1,0 hours for abacavir and lamivudine respectively.  
Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4,26 μg/ml  
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584.  
and the mean AUC∞ is 11,95 μg.h/ml. Following multiple-dose oral  
administration of lamivudine 300 mg once daily for seven days the mean steady-  
state Cmax is 2,04 μg/ml and the mean AUC24 is 8,87 μg.h/ml.  
585.  
586.  
587.  
588.  
589.  
590.  
591.  
592.  
593.  
594.  
595.  
596.  
597.  
598.  
599.  
600.  
601.  
602.  
603.  
604.  
605.  
606.  
607.  
608.  
Metabolism:  
Abacavir is principally metabolised by the liver with less than 2 % of the  
administered dose being renally excreted, unchanged. The main pathways of  
metabolism are by alcohol dehydrogenase and by glucuronidation to produce the  
5’-carboxylic acid and 5’-glucuronide which account for about 66 % of the dose in  
the urine.  
Lamivudine is metabolised intracellularly to the active 5’-triphosphate which has  
an intracellular half-life of 16 – 19 hours. Lamivudine is predominately cleared  
unchanged by renal excretion. The likelihood of metabolic interactions with  
lamivudine is low due to the small extent of hepatic metabolism (less than 10 %).  
Distribution:  
Following intravenous administration, the apparent volume of distribution of  
abacavir is about 0,8 l/kg, indicating that abacavir penetrates freely into body  
tissues. Plasma protein binding studies in vitro indicate that abacavir binds only  
low to moderately (~49 %) to human plasma proteins at therapeutic  
concentrations.  
The mean volume of distribution of lamivudine from intravenous studies has been  
reported as 1,3 l /kg. Lamivudine exhibits linear pharmacokinetics over the  
therapeutic dose range and displays low plasma protein binding (less than 36 %).  
This indicates a low likelihood for interactions with other medicines through  
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609.  
plasma protein binding displacement.  
610.  
611.  
612.  
613.  
614.  
615.  
616.  
617.  
618.  
619.  
620.  
621.  
622.  
623.  
624.  
625.  
626.  
627.  
628.  
629.  
630.  
631.  
632.  
633.  
Data shows that abacavir and lamivudine penetrate the central nervous system  
(CNS) and reach the cerebrospinal fluid (CSF). Studies in HIV infected patients  
have shown good penetration of abacavir into the cerebrospinal fluid (CSF), with  
a CSF to plasma AUC ratio of between 30 to 44 %. The true extent of penetration  
or relationship with any clinical efficacy is unknown.  
Co-administration of zidovudine results in a 13 % increase in zidovudine  
exposure and a 28 % increase in peak plasma levels. This is not considered to  
be of significance to patient safety and therefore no dosage adjustments are  
necessary.  
Elimination:  
The mean half-life of abacavir is about 1,5 hours. Following multiple oral doses of  
abacavir 300 mg twice a day, there is no significant accumulation of abacavir.  
Elimination of abacavir is via hepatic metabolism with subsequent excretion of  
metabolites primarily in the urine. The metabolites and unchanged abacavir  
account for about 83 % of the administered abacavir dose in the urine. The  
remainder is eliminated in the faeces.  
The observed lamivudine half-life of elimination is 5 to 7 hours. The mean  
systemic clearance of lamivudine is approximately 0,32 l /h/kg, predominantly by  
renal clearance of more than 70 % via active tubular secretion, but hepatic  
metabolism, is less than 10 %.  
Pharmacokinetics in special populations:  
Hepatically impaired - Pharmacokinetic data has been obtained for abacavir  
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634.  
and lamivudine alone. Abacavir is metabolised primarily by the liver. The  
pharmacokinetics of abacavir have been studies in patients with mild hepatic  
impairment (Child-Plugh score 5 to 6) and results show that dosage reduction of  
abacavir is required in these patients. The separate preparation of abacavir  
should therefore be used to treat these patients.  
635.  
636.  
637.  
638.  
639.  
640.  
641.  
642.  
643.  
644.  
645.  
646.  
647.  
648.  
649.  
650.  
651.  
652.  
653.  
654.  
655.  
656.  
657.  
658.  
The pharmacokinetics of abacavir have not been studied in patients with  
moderate or severe hepatic impairment. Plasma concentrations of abacavir are  
expected to be variable and substantially increased in these patients.  
HETERUAM is therefore contra-indicated in patients with moderate and severe  
hepatic impairment.  
Data obtained for lamivudine in patients with moderate to severe hepatic  
impairment show that the pharmacokinetics are not significantly affected by  
hepatic dysfunction.  
Renally impaired: Abacavir is primarily metabolised by the liver, with  
approximately 2 % of abacavir excreted unchanged in the urine. The  
pharmacokinetics of abacavir in patients with end-stage renal disease is similar  
to patients with normal renal function.  
Studies with lamivudine show that plasma concentrations (AUC) are increased in  
patients with renal dysfunction due to decreased clearance. Dose reduction is  
required for patients with creatinine clearance of less than 50 ml/min, therefore  
the separate preparation of lamivudine should be used to treat these patients.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
659.  
660.  
661.  
662.  
663.  
664.  
665.  
666.  
667.  
668.  
669.  
670.  
671.  
672.  
673.  
674.  
675.  
676.  
677.  
678.  
679.  
680.  
681.  
682.  
683.  
•
•
•
•
•
•
Abacavir sulphate  
Lamivudine  
Microcrystalline cellulose  
Magnesium stearate  
Sodium starch glycolate  
Colloidal silicon dioxide  
Composition of Opadry orange YS-1-13065-A  
•
•
•
•
•
Hypromellose E464  
Titanium dioxide E171  
Macrogol/Polyethylene Glycol 400 E1521  
FD&C Yellow#6/Sunset yellow FCF aluminum lake E110  
Polysorbate 80 E433  
Composition of Instacoat Universal Orange A05G24486  
•
•
•
•
•
Hypromellose E464  
Titanium dioxide E171  
Macrogol/Polyethylene Glycol 400 E1521  
FD&C Yellow#6/Sunset yellow FCF aluminum lake E110  
Polysorbate 80 E433  
6.2 Incompatibilities  
Not applicable  
6.3 Shelf life  
36 months  
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Product proprietary name: HETERUAM 600/300 mg  
Dosage form and strength: Film coated tablet and 600/300 mg  
684.  
6.4 Special precautions for storage  
685.  
686.  
687.  
688.  
689.  
690.  
691.  
692.  
693.  
694.  
695.  
696.  
697.  
698.  
699.  
700.  
701.  
702.  
703.  
704.  
705.  
706.  
707.  
708.  
Store in the original packaging at or below 30 °C.  
Keep the bottle tightly closed. Protect from moisture.  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
28’s and 30’s count HDPE container  
High density polyethylene container 100 cc with 38 mm Neck (heavy weight) with  
a child resistant plastic caps with pulp liners 38 mm with a desiccant canister 2,0  
g, silica gel  
10’s WO PVC/PVdC blister pack  
White opaque forming film, width 98 mm (250 microns PVC / 120 PVdc) with  
0,025 x 96 mm, plain aluminum foil(hard tempered) with 7 GSM HSL coating on  
bright side.  
10’s Alu /Alu blister pack  
Cold forming film, width 188 mm (60 microns PVC / 45 microns aluminum foil / 25  
micron OPA) DMF 0,025 x 186 mm, plain aluminum foil (hard tempered) with 7  
GSM HSL coating on bright side (DMF).  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
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709.  
Hetero Drugs South Africa (Pty) Ltd.,  
Waterfall Corporate Campus,  
Building 2, First Floor,  
74 Waterfall Drive,  
Midrand,  
710.  
711.  
712.  
713.  
714.  
715.  
716.  
717.  
718.  
719.  
720.  
721.  
722.  
723.  
2066  
8 REGISTRATION NUMBER  
48/20.2.8/1243  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
29 July 2016  
10 DATE OF REVISION OF THE TEXT  
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