Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: VALHET 450  
Dosage form and strength: Film coated tablets and 450 mg  
APPROVED PROFESSIONAL INFORMATION FOR VALHET 450  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
VALHET 450 (film-coated tablets)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film-coated tablet contains valganciclovir hydrochloride equivalent to 450 mg of  
valganciclovir.  
Sugar free.  
For full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
Pink, oval, biconvex, film-coated tablets, debossed with 'J' on one side and '156' on the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
VALHET is indicated for:  
•
The treatment of cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome  
(AIDS) patients.  
•
The prevention of CMV disease in solid organ transplant patients who are at risk i.e., donor  
seropositive and recipient seronegative.  
4.2 Posology and method of administration  
Posology  
The bioavailability of ganciclovir from VALHET tablets is up to 10-fold higher than from ganciclovir  
capsules, therefore the dosage and administration of VALHET tablets should be closely followed.  
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The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is  
equivalent to a dose of 900 mg valganciclovir tablets (two VALHET tablets).  
Treatment of cytomegalovirus (CMV) retinitis  
Standard dosage in adults  
Induction treatment of CMV retinitis  
For patients with active CMV retinitis, the recommended dose is 900 mg valganciclovir (two  
VALHET tablets) twice a day for 21 days. Prolonged induction treatment may increase the risk of  
bone marrow toxicity.  
Maintenance treatment of CMV retinitis  
Following induction treatment, or in patients with inactive CMV retinitis, the recommended dose is  
900 mg valganciclovir (two VALHET tablets) once daily. Patients whose retinitis worsens may  
repeat induction treatment; however, consideration should be given to the possibility of viral  
medicine resistance.  
Prevention of CMV disease in solid organ transplantation  
For kidney transplant patients, the recommended dose is 900 mg (two VALHET tablets) once daily  
depending on creatinine clearance, starting within 10 days of transplantation until 200 days post-  
transplantation.  
For patients who have received a solid organ transplant other than the kidney, the recommended  
dose is 900 mg (two VALHET tablets) daily, starting within 10 days of transplantation until 100  
days post transplantation.  
Special populations  
Patients with renal impairment  
Serum creatinine levels or creatinine clearance should he monitored carefully. Dosage adjustment  
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is required for adult patients based on creatinine clearance, as shown in table 1 below.  
Creatinine clearance (mL/min) is calculated from serum creatinine by the following formulae:  
CrCl (mL/min) = (140 – age) x (Wt [kg]) x constant*  
SCr [μmol/L]  
*Constant = 1,23 for males and 1,04 for females (0,85 x 1,23 = 1,04) The South African Renal  
Society recommends simplifying the above formula by omitting the constant of 1,23 for males  
CrCl (mL/min) = (140 – age) x (Wt [kg]) x 0,85 (if female)  
SCr [μmol/L]  
CrCl = creatinine clearance  
SCr = serum creatinine  
Table 1: VALHET film-coated tablet dose for renally impaired patients  
CrCl (mL/min)  
Induction dose of  
Maintenance/prevention  
dose of VALHET film-coated  
tablet  
VALHET film-coated  
≥ 60  
900 mg twice daily  
900 mg once daily  
450 mg once daily  
450 mg every 2 days  
450 mg twice weekly  
Not recommended  
40 – 59  
25 – 39  
10 – 24  
< 10  
450 mg twice daily  
450 mg once daily  
450 mg every 2 days (tablets)  
Not recommended  
Patients undergoing haemodialysis  
For patients on haemodialysis (CrCl < 10 mL/min) a dose recommendation cannot be given. Thus,  
VALHET film-coated tablets should not be used in these patients (see sections 4.4 and 5.2).  
Patients with severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia  
Patients with severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia, bone  
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marrow depression and aplastic anaemia have been observed in patients treated with VALHET  
(and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500  
cells/µL or the platelet count is less than 25000/µL or the haemoglobin is less than 8 g/dL.  
Elderly  
Safety and efficacy have not been established.  
Paediatric population  
Safety and efficacy have not been established in adequate and well-controlled clinical studies.  
Method of administration  
VALHET is administered orally and should be taken with food.  
Precautions to be taken before handling or administering the VALHET  
The tablets should not be broken or crushed. Since VALHET is considered a potential teratogen  
and carcinogen in humans, caution should be observed in handling broken tablets (see section  
4.4). Avoid direct contact of broken or crushed tablets with skin or mucous membranes. If such  
contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with sterile water, or  
plain water if sterile water is unavailable.  
4.3 CONTRAINDICATIONS  
•
Hypersensitivity to valganciclovir or ganciclovir, or to any of the excipients of VALHET  
(listed in section 6.1).  
•
Due to the similarity of chemical structure of VALHET and that of aciclovir and valaciclovir,  
a cross-hypersensitivity reaction between these medicines is possible.  
4.4 Special warnings and precautions for use  
Severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia, bone marrow  
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depression and aplastic anaemia have been observed in patients treated with VALHET (and  
ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500  
cells/µL, or the platelet count is less than 25 000/µL, or the haemoglobin level is less than 8 g/dL.  
When extending prophylaxis beyond 100 days the possible risk of developing leukopenia and  
neutropenia should be considered. Valganciclovir should be used with caution in patients with pre-  
existing haematological cytopenia or a history of medicine-related haematological cytopenia and in  
patients receiving radiotherapy. It is recommended that complete blood counts and platelet counts  
be monitored during therapy.  
In patients with severe leukopenia, neutropenia, anaemia and/or thrombocytopenia, it is  
recommended that treatment with haematopoietic growth factors and/or dose interruption be  
considered.  
Porphyria. The Drug Database for Acute Porphyria, compiled by the Norwegian Porphyria Centre  
(NAP O S) and the Porphyria Centre Sweden, classifies valganciclovir as not porphyrinogenic; it  
may be used as a drug of first choice and no precautions are needed.  
Safety and efficacy in children have not been established.  
The bioavailability of ganciclovir from VALHET is up to 10-fold higher than from ganciclovir  
capsules. VALHET cannot be substituted for ganciclovir capsules on a one-to-one basis. Patients  
switching from ganciclovir capsules should be advised of the risk of over dosage if they take more  
than the prescribed number of VALHET tablets (see section 4.2).  
In patients with impaired renal function, dosage adjustments based on creatinine clearance are  
required (see section 4.2).  
VALHET film coated tablets should not be used in patients on haemodialysis.  
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For patients receiving haemodialysis dose recommendations for VALHET film-coated tablets  
cannot be given. This is because an individual dose of VALHET required for these patients is less  
than the 450 mg tablet strength. Thus, VALHET film-coated tablets should not be used in these  
patients (see section 4.2).  
Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term.  
Dosage adjustments in special populations:  
•
•
In patients with impaired renal function, dosage adjustments based on creatinine clearance  
are required. (see section 4.2). For patients on haemodialysis (CrCI < 10 ml/min) a tablet  
dose recommendation cannot be given.  
Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin  
concomitantly. These medicines should not be used concomitantly unless the potential  
benefit outweighs the potential risks. (see section 4.5).  
•
•
•
•
Zidovudine and VALHET may cause neutropenia and anaemia; some patients may not  
tolerate concomitant therapy at full dosage (see section 4.5).  
Didanosine plasma concentrations may increase during concomitant use with VALHET,  
therefore patients should be closely monitored for didanosine toxicity (see section 4.5).  
Concomitant use of other medicines that are known to be myelosuppressive or associated  
with renal impairment with VALHET may result in added toxicity (see section 4.5).  
Since VALHET is considered a potential teratogen and carcinogen in humans. If a broken  
tablet makes direct contact with skin, the area should be washed thoroughly with soap and  
water. If the solution gets into the eye, the eye should immediately be thoroughly washed  
with water.  
4.5 Interaction with other medicines and other forms of interaction  
The following medicines, valaciclovir, didanosine, nelfinavir, ciclosporin, omeprazole and  
mycophenolate mofetil did not affect the permeability of valganciclovir (rat in-situ model).  
Valganciclovir as in VALHET is metabolised to ganciclovir. Therefore, medicine interactions  
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associated with ganciclovir will be expected for VALHET.  
Medicine interactions with ganciclovir  
Imipenem-cilastatin:  
Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin. These  
medicines should not be used concomitantly unless the potential benefit overweighs the potential  
risks.  
Probenecid:  
Probenecid given with oral ganciclovir may reduce renal clearance of ganciclovir (20 %) leading to  
statistically significantly increase exposure (40 %). These changes were consistent with a  
mechanism of interaction involving competition for renal tubular excretion. Therefore, patients  
taking probenecid and VALHET should be closely monitored for ganciclovir toxicity.  
Zidovudine:  
When zidovudine was given in the presence of oral ganciclovir there was a small (17 %), but  
statistically significant increase in the AUC of zidovudine. There was also trend towards lower  
ganciclovir concentrations when administered with zidovudine, although this was not statistically  
significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia  
and anaemia, some patients may not tolerate concomitant therapy at full dosage.  
Didanosine:  
Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir  
(both intravenous and oral). At ganciclovir oral doses of 3 and 6 g/day, an increase in the AUC of  
didanosine ranging from 84 to 124 % has been observed and likewise at intravenous doses of 5  
and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67 % has been  
observed. This increase cannot be explained by competition for renal tubular secretion, as there  
was an increase in the percentage of didanosine dose excreted. This increase could arise from  
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either increased bioavailability or decreased metabolism. There was no clinically significant effect  
on ganciclovir concentrations. However, given the increase in didanosine plasma concentrations in  
the presence of ganciclovir, patients should be closely monitored for didanosine toxicity.  
Mycophenolate Mofetil:  
Based on the results of a single dose administration study of recommended doses of oral  
mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal  
impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration  
of these agents (which have the potential to compete for renal tubular secretion) will result in  
increase in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No  
substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose  
adjustment is not required. ln patients with renal impairment in which MMF and ganciclovir are co-  
administered, the dose recommendation of ganciclovir should be observed and patients monitored  
carefully.  
Zalcitabine:  
Zalcitabine increased the AUC0-8 of oral ganciclovir by 13 %. There were no statistically significant  
changes in any of the other pharmacokinetic parameters assessed. Additionally, there were no  
clinical relevant changes in zalcitabine pharmacokinetics in the presence of oral ganciclovir  
although a small increase in the elimination rate constant was observed.  
Both valganciclovir and zalcitabine have the potential to cause peripheral neuropathy and patients  
should be monitored for such events.  
Stavudine:  
No statistically significant pharmacokinetic interactions were observed when stavudine and oral  
ganciclovir were given in combination.  
Trimethoprim:  
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Trimethoprim statistically significantly decreased the renal clearance of oral ganciclovir by 16,3 %  
and this was associated with a statistically significant decrease in the terminal elimination rate and  
the corresponding increase in half-life by 15 %. However, these changes are unlikely to be clinically  
significant, as AUC0-8 and Cmax were unaffected.  
The only statistically significant change in trimethoprim pharmacokinetic parameters when co-  
administered with ganciclovir was a 12 % increase in Cmax  
.
However, this is unlikely to be of clinical significance and no dose adjustment is recommended.  
Ciclosporin:  
There was no evidence that introduction of ganciclovir affects the pharmacokinetics of ciclosporin  
based on the comparison of ciclosporin trough concentrations. However, there was some evidence  
of increases in the maximum serum creatinine value observed following initiation of ganciclovir  
therapy.  
Other potential medicine interactions:  
Toxicity may be enhanced when ganciclovir is co-administered with, or is given immediately before  
or after, other medicines that inhibit replication of rapidly dividing cell populations such as occur in  
the bone marrow, tested and germinal layers of the skin and gastrointestinal mucosa, or that are  
associated with renal impairment (such as dapsone, pentamidine, flucytosine, vincristine,  
vinblastine, adriamycin, amphotericin B, sulfamethoxazole-trimethoprim combinations, nucleoside  
analogues and hydroxyurea) therefore these medicines should be considered for contaminant use  
with valganciclovir only if the potential benefits outweigh the potential risks.  
Since ganciclovir is excreted through the kidney via glomerular filtration and active tubular  
secretion, coadministration of valganciclovir with antiviral medicines that share the tubular secretion  
pathway may change the plasma concentrations of valganciclovir and/or the coadministered  
medicine. Some examples include nucleoside analogue reverse-transcriptase inhibitors (NRTIs)  
(including those used for HBV therapy), e.g. lamivudine, emtricitabine, tenofovir, adefovir and  
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entecavir. The renal clearance of ganciclovir may also be inhibited due to nephrotoxicity caused by  
medicines such as cidofovir, foscarnet, NRTIs (e.g. tenofovir, adefovir). Concomitant use of  
valganciclovir with any of these medicines should not be considered.  
4.6 Fertility, pregnancy, and lactation  
Contraception in males and females  
Women of childbearing potential must be advised to use effective contraception during treatment.  
Male patients should be advised to practice barrier contraception during, and for at least 90 days  
following treatment with VALHET.  
Pregnancy  
The safety of VALHET for use in pregnant women has not been established.  
In animal studies, ganciclovir was shown to be teratogenic and embryotoxic. Prior to the initiation of  
valganciclovir treatment patients should be advised of the potential risks to the foetus.  
Breastfeeding  
Women using VALHET should not breastfeed their infants.  
Pre-and postnatal development has not been studied with VALHET, but the possibility of  
ganciclovir being excreted in breast milk and causing serious adverse reactions in the breastfed  
infant cannot be excluded.  
Fertility  
In animal studies ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and  
carcinogenic and a suppressor of female fertility. VALHET should, therefore be considered a  
potential teratogen and carcinogen in humans with the potential to cause birth effects and cancers.  
It is also considered that VALHET causes temporary or permanent inhibition of spermatogenesis.  
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4.7 Effects on ability to drive and use machines  
Convulsions, dizziness and confusion have been reported with the use of VALHET and or  
ganciclovir. If they occur, such effects may affect tasks requiring alertness, including the patient's  
ability to drive and operate machinery.  
4.8 Undesirable effects  
a) Summary of the safety profile  
Valganciclovir is a prodrug of ganciclovir. It is rapidly converted to ganciclovir after oral  
administration. The side effects known to be associated with ganciclovir usage can therefore be  
expected to occur with VALHET administration.  
All of the undesirable effects observed in valganciclovir clinical studies have been previously  
observed with ganciclovir.  
The most frequently reported adverse drug reactions following oral administration of valganciclovir  
in adults are neutropenia, anaemia and diarrhoea.  
Severe thrombocytopenia may be associated with potentially life-threatening bleeding.  
b) Tabulated summary of adverse reactions  
System organ class  
Frequency  
Adverse event  
Infections and Infestations  
Frequent  
Candida  
infections  
including  
(bacteraemia,  
urinary tract  
oral  
candidiasis,  
viraemia),  
sepsis  
cellulitis,  
infection, influenza  
Neutropenia,  
Blood  
and  
lymphatic  
Frequent  
anaemia,  
system disorders  
thrombocytopenia,  
pancytopenia  
leukopenia,  
Less frequent  
Bone marrow depression, aplastic  
anaemia,  
agranulocytosis,  
granulocytopenia  
Hypersensitivity  
Anaphylactic reaction  
Immune system disorders  
Frequent  
Less frequent  
Frequent  
Metabolism and nutrition  
Decreased appetite, decreased weight  
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disorders  
Psychiatric disorders  
Nervous system disorders  
Eye disorders  
Frequent  
Depression,  
insomnia  
anxiety,  
confusion,  
disorder,  
Less frequent  
Frequent  
Agitation,  
psychotic  
hallucinations, abnormal thinking  
Headache, dysgeusia, hypoaesthesia,  
paraesthesia, peripheral neuropathy,  
dizziness, convulsion  
Less frequent  
Frequent  
Tremor  
Visual  
disturbance,  
conjunctivitis,  
macular oedema, retinal detachment,  
vitreous floaters, eye pain  
Ear pain  
Ear  
and  
labyrinth  
Frequent  
disorders  
Less frequent  
Frequent  
Deafness  
Cardiac disorders  
Chest pain  
Less frequent  
Frequent  
Dysrhythmias  
Vascular disorders  
Hypotension  
Respiratory, thoracic, and  
mediastinal disorders  
Gastrointestinal disorders  
Frequent  
Dyspnoea, cough  
Frequent  
Diarrhoea,  
nausea,  
vomiting,  
abdominal pain, upper abdominal pain,  
dyspepsia,  
dysphagia,  
constipation,  
abdominal  
flatulence,  
distension,  
mouth ulcerations, pancreatitis  
Abnormal hepatic function, increased  
blood alkaline phosphatase, increased  
aspartate aminotransferase, increased  
alanine aminotransferase  
Hepato-biliary disorders  
Frequent  
Skin and subcutaneous  
tissue disorders  
Frequent  
Dermatitis, pruritus, night sweat, rash  
Alopecia, urticaria, dry skin  
Less frequent  
Frequent  
Musculoskeletal  
connective  
and  
Spasm, back pain, myalgia, arthralgia,  
muscle cramps  
tissue  
disorders  
Renal  
and  
urinary  
Frequent  
Decreased creatinine clearance, renal  
impairment  
disorders  
Less frequent  
Haematuria, renal failure  
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Reproductive system and  
breast disorders  
Less frequent  
Frequent  
Male infertility  
General  
disorders  
and  
site  
Night sweats, fatigue, pyrexia rigors,  
pain, malaise, asthenia  
administration  
conditions  
Investigations  
Frequent  
Decreased weight, increased blood  
creatinine, abnormal liver function tests  
c) Description of selected adverse reactions  
The risk of neutropenia is not predictable on the basis of the number of neutrophils before  
treatment. Neutropenia usually occurs during the first or second week of induction therapy. The cell  
count usually normalises within 2 to 5 days after discontinuation of the drug or dose reduction (see  
section 4.4).  
Thrombocytopenia  
Patients with low baseline platelet counts (< 100,000 /μL) have an increased risk of developing  
thrombocytopenia. Patients with iatrogenic immunosuppression due to treatment with  
immunosuppressive medicines are at greater risk of thrombocytopenia than patients with AIDS  
(see section 4.4). Severe thrombocytopenia may be associated with potentially life-threatening  
bleeding.  
Influence of treatment duration or indication on adverse reactions  
Severe neutropenia (ANC <500/μL) is seen more frequently in CMV retinitis patients (14%)  
undergoing treatment with valganciclovir, intravenous or oral ganciclovir than in solid organ  
transplant patients receiving valganciclovir or oral ganciclovir. In patients receiving valganciclovir or  
oral ganciclovir until Day 100 post-transplant, the incidence of severe neutropenia was 5% and 3%  
respectively, whilst in patients receiving valganciclovir until Day 200 post-transplant the incidence  
of severe neutropenia was 10%. There was a greater increase in serum creatinine seen in solid  
organ transplant patients treated until Day 100 or Day 200 post-transplant with both valganciclovir  
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and oral ganciclovir when compared to CMV retinitis patients. However, impaired renal function is a  
feature common in solid organ transplantation patients. The overall safety profile of VALHET did  
not change with the extension of prophylaxis up to 200 days in high-risk kidney transplant patients.  
Leukopenia was reported with a slightly higher incidence in the 200 days arm while the incidence of  
neutropenia, anaemia and thrombocytopenia were similar in both arms.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of VALHET is important. It allows  
continued monitoring of the benefit/risk balance of VALHET. Health care providers are requested  
to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X  
SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website or to the Holder of  
certificate of registration through the mail: pvg.cdma@heterogroups.com.  
4.9 Overdose  
It is expected that an overdose of VALHET could also possibly result in increased renal toxicity.  
Overdose experience with IV ganciclovir:  
The majority of patients experienced one or more of the following adverse events:  
•
Haematological toxicity: pancytopenia, bone marrow depression, medullary aplasia,  
leukopenia, neutropenia, granulocytopenia.  
•
•
Hepatotoxicity: hepatitis, liver function disorder.  
Renal toxicity: worsening of haematuria in a patient with pre-existing renal impairment,  
acute renal failure, and elevated creatinine.  
•
•
Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting.  
Neurotoxicity: generalised tremor, convulsion.  
Treatment:  
Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who  
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receive an overdose of VALHET.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacological classification: A 20.2.8 Antiviral agents  
Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse  
transcriptase inhibitors, ATC code: J05A B14  
Mechanism of action  
Valganciclovir is an L-valyl ester (prodrug) of ganciclovir. After oral administration, valganciclovir is  
rapidly and extensively metabolised to ganciclovir by intestinal and hepatic esterases. Ganciclovir  
is a synthetic analogue of 2’-deoxyguanosine and inhibits replication of herpes viruses in vitro and  
in vivo. In vitro sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex  
virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV-8),  
Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).  
Ganciclovir requires phosphorylation to its triphosphate form for antiviral activity.  
In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the  
viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce  
ganciclovir triphosphate, which is then slowly metabolised intercellularly. Triphosphate metabolism  
has been shown to occur in HSV- and HSMV-infected cells with half-lives of 18 and between 6 and  
24 hours respectively, after the removal of extracellular ganciclovir. As phosphorylation is largely  
dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected  
cells.  
The virus static activity of ganciclovir is due to inhibition of viral DNA synthesis by:  
a) ganciclovir triphosphate competitively inhibiting the incorporation of Deoxyguanosine-  
triphosphate (dGTP) into DNA by viral DNA polymerase, and  
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b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very  
limited, further viral DNA elongation.  
Viral resistance:  
Viral-resistance to ganciclovir can arise after chronic dosing with valganciclovir by selection of  
mutations in either the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation  
and/or the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are  
resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene are resistant to  
ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.  
Antiviral activity:  
The in vitro anti-viral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0,08  
µM (0,02 µg/mL) to 14 µM (3,5 µg/mL).  
5.2 Pharmacokinetic properties  
Absorption  
Valganciclovir is a prodrug of ganciclovir. It is well absorbed from the gastrointestinal tract and  
rapidly and extensively metabolised in the intestinal wall and liver to ganciclovir. The absolute  
bioavailability of ganciclovir from valganciclovir is approximately 60 %. Systemic exposure to  
valganciclovir is transient and low. Valganciclovir allows systemic exposure of ganciclovir similar to  
that achieved with recommended doses of IV ganciclovir.  
AUC24 and Cmax for valganciclovir are approximately 1 % and 3 % of those of ganciclovir,  
respectively. For comparison, the bioavailability of ganciclovir after administration of 1 000 mg oral  
ganciclovir (as capsules) is 6 – 8 %.  
Valganciclovir in HIV+, CMV+ patients:  
Systemic exposure of HIV+, CMV+ patients after twice daily administration of ganciclovir and  
valganciclovir for one week is:  
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Dosage form and strength: Film coated tablets and 450 mg  
Parameter  
Ganciclovir  
Valganciclovir (900 mg, p.o.)  
(5 mg/kg, i.v)  
Ganciclovir  
Valganciclovir  
0,37 ± 0,22  
0,18 ± 0,06  
AUC (0 – 12 h)  
(µg.h/mL)  
28,0 ± 9,0  
10,4 ± 4,9  
32,8 ± 2,1  
6,7 ± 2,1  
Cmax (µg/mL)  
The efficacy of ganciclovir in increasing the time to progression of CMV retinitis has been shown to  
correlate with systemic exposure (AUC).  
Valganciclovir in solid organ transplant patients:  
Steady state systemic exposure of solid organ transplant patients to ganciclovir after daily oral  
administration of ganciclovir and valganciclovir is:  
Parameter  
Ganciclovir  
Valganciclovir  
(900 mg, once daily)  
Ganciclovir  
(1000 mg three daily)  
AUC (0 – 24 h)  
(µg.h/mL)  
28,0 ± 10,9  
1,4 ± 0,5  
46,3 ± 15,2  
5,3 ± 1,5  
Cmax (µg/mL)  
The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar  
after oral administration of valganciclovir according to the renal function dosing algorithm.  
Following the administration of valganciclovir as an oral solution, equivalent systemic ganciclovir  
exposures were obtained compared to the tablet formulation.  
Food: When valganciclovir was given with food at the recommended dose of 900 mg, increases  
were seen in both mean ganciclovir AUC24 (± 30 %) and mean ganciclovir Cmax values (± 14 %), it is  
recommended that valganciclovir be administered with food.  
Distribution  
Plasma protein binding of ganciclovir was 1 – 2 % over concentrations of 0,5 and 51 µg/mL. The  
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Product proprietary name: VALHET 450  
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steady state volume of distribution of ganciclovir after IV administration was 0,680 ± 0,161 L/kg.  
Biotransformation  
Valganciclovir is rapidly and extensively metabolised to ganciclovir, no other metabolites have been  
detected. No metabolite of orally administered radiolabelled ganciclovir (1 000 mg single dose)  
accounted for more than 1 – 2 % of the radioactivity recovered in the faeces and urine.  
Elimination  
The major route of elimination of valganciclovir as ganciclovir is renal excretion, by glomerular  
filtration and active tubular secretion. Renal clearance accounts for 81,5 % ± 22 % of the systemic  
clearance of valganciclovir. The half-life of ganciclovir from valganciclovir is 4,1 ± 0,9 hours in HIV-  
and CMV-seropositive patients.  
Special populations  
Renal impairment:  
Decreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with an  
increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients  
(see section 4.2).  
Haemodialysis:  
For patients receiving haemodialysis (CrCl < 10 mL/min); it is recommended that IV ganciclovir is  
used. The individual dose of ROLIXIRD 450 MG required for these patients is less than the 450 mg  
tablet strength. Approximately half of the ganciclovir present at the start of dialysis is removed  
during dialysis. The mean intra-dialysis half-life and mean interdialysis half-life is estimated to be  
3,47 h and 51,0 h respectively. However, for patients receiving haemodialysis (CrCl < 10 mL/min)  
valganciclovir oral solution is recommended to provide an individualised dose (see section 4.2).  
Hepatic impairment:  
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Product proprietary name: VALHET 450  
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The pharmacokinetics of valganciclovir in suitable liver transplant recipients were investigated in  
one open-label 4-crossover study. The absolute bioavailability of ganciclovir from valganciclovir  
following a single dose of 900 mg valganciclovir under fed conditions was approximately 60 %, in  
agreement with estimates obtained in other patient populations. Ganciclovir AUC0-24 was  
comparable to that achieved by 5 mg/kg IV ganciclovir in liver transplant recipients.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
Crospovidone  
Microcrystalline cellulose  
Povidone  
Stearic acid  
Opadry pink 15B24005  
Hypromellose E464  
Titanium dioxide E171  
Macrogol/peg E1521  
Red iron oxide E172  
Polysorbate 80 E433  
6.2 Incompatibilities  
Not applicable.  
6.3 Shelf life  
36 months  
6.4 Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
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Product proprietary name: VALHET 450  
Dosage form and strength: Film coated tablets and 450 mg  
Bottle must be kept well-closed.  
Keep the blisters in the outer carton until required for use.  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
60’s count HDPE container  
60 film-coated tablets are packed in a white HDPE bottle with a white, opaque polypropylene, child  
resistant screw closure, and purified cotton is used as filler. The bottle will be packed inside an  
outer carton box.  
Alu - Alu blister pack  
Tablets packed in aluminium blister pack, and blisters packed in a carton.  
Pack sizes  
1 × 10’s; 3 x 6’s or 7 x 6’s Aluminium blister packs are packed inside an outer carton box.  
6.6 Special precautions for disposal and other handling  
None  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No.2, First Floor  
74 Waterfall Drive  
Midrand, 2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@hetero.com  
8 REGISTRATION NUMBER  
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51/20.2.8/0197  
9 DATE OF FIRST AUTHORISATION  
25 September 2018  
DATE OF RENEWAL OF AUTHORISATION  
13 January 2025  
10 DATE OF REVISION OF THE TEXT  
10 February 2025  
10 February 2025  
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