Vacyte 50 Mg Film-Coated Tablets

VALCYTE is indicated for

• The treatment of cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome (AIDS) patients.
• The prevention of CMV disease in adult and paediatric solid organ transplant (SOT) patients who are at risk i.e. donor seropositive and recipient seronegative.

Strict adherence to dosage recommendations is essential to avoid overdose. VALCYTE is administered orally and should be taken with food. The bioavailability of ganciclovir from VALCYTE is up to 10-fold higher than from ganciclovir capsules, therefore the dosage and administration of VALCYTE tablets or powder for oral solution should be closely followed. The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is equivalent to a dose of 900 mg valganciclovir tablets (two VALCYTE 450 mg tablets). An oral dosing dispenser with 0.5 mL graduations (25 mg) to 10 mL (500 mg) with 25 mg graduations up to 500 mg is provided with the powder for oral solution. It is recommended that this dispenser is used to measure and administer the dose.

Standard dosage

Treatment of cytomegalovirus (CMV) retinitis

Adult Patients

Induction treatment of CMV retinitis

For patients with active CMV retinitis, the recommended dose is 900 mg valganciclovir (two VALCYTE 450 mg tablets) twice a day for 21 days taken with food. 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 VALCYTE 450 mg tablets) once daily taken with food. Patients whose retinitis worsens may repeat induction treatment; however, consideration should be given to the possibility of viral drug resistance. The duration of maintenance treatment should be determined on an individual basis.

Paediatric Patients

The safety and efficacy of VALCYTE in the treatment of CMV retinitis have not been established in adequate and well-controlled clinical studies in paediatric patients.

Prevention of CMV disease in solid organ transplantation

Adult Patients

For kidney transplant patients, the recommended dose is 900 mg valganciclovir (two VALCYTE 450 mg 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 valganciclovir (two VALCYTE 450 mg tablets) once daily, starting within 10 days of transplantation until 100 days post transplantation.

Paediatric Patients

In paediatric solid organ transplant patients, aged from birth, who are at risk of developing CMV disease, the recommended once daily dose of VALCYTE is based on body surface area (BSA) and creatinine clearance (Clcr) derived from Schwartz formula (ClcrS), and is calculated using the equation below:

Paediatric Dose (mg) = 7 x BSA x ClcrS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1,73 m2, then a maximum value of 150 mL/min/1,73 m2 should be used in the equation.

3600 ) ( ) ( ) 2 kg Weight x cm Height m BSA Mosteller = ) / ( ) ( ) 73 . 1 / min / ( 2 dl mg Creatinine Serum cm Height x k m ml Clearance Creatinine Schwartz = Where k = 0,45 for patients aged < 2 years, 0,55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and 0,7 for boys aged 13 to 16 years.

Refer to adult dosing for patients older than 16 years of age.

u2212 The k values provided are based on the Jaffe method of measuring serum creatinine and may require correction when enzymatic methods are used.

u2212 * A lowering of k value may also be necessary for appropriate sub-populations.

For paediatric kidney transplant patients, the recommended once daily mg dose (7 x BSA x ClcrS) should start within 10 days post-transplantation and continue until 200 days post-transplantation.

For paediatric patients who have received a solid organ transplant other than kidney, the recommended once daily mg dose (7 x BSA x ClcrS) should start within 10 days post-transplantation and continue until 100 days post-transplantation.

All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. The oral dispenser is graduated in mL. A 50 mg dose is equivalent to 1 mL:

Valganciclovir dose VALCYTE for Oral Solution to be administered

• 50 mg 1 mL
• 75 mg 1,5 mL
• 100 mg 2 mL
• 500 mg 10 mL

If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. The oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, VALCYTE tablets may be used if the calculated doses are within 10 % of available tablet doses, and the patient is able to swallow tablets. For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. It is recommended to monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.

Special Dosage Instructions

Paediatric Patients

Dosing of paediatric SOT patients is individualised based on a patientu2019s renal function and size (see section 4.2). A higher risk of haematological cytopenias in neonates and infants warrants careful monitoring of blood counts in these age groups. Monitoring of liver function abnormalities, renal function and gastrointestinal fluid loss is also recommended in paediatric patients.

Elderly Patients

Safety and efficacy have not been established in this patient population. No studies have been conducted in adults older than 65 years of age. Since renal clearance decreases with age, VALCYTE should be administered to elderly patients with special consideration of their renal status (see Table 1 and section 5.2).

Adult patients with renal impairment

Serum creatinine levels or estimated creatinine clearance should be monitored carefully. Dosage adjustment is required for adult patients based on creatinine clearance, as shown in tables 1 and 2 below.

Estimated creatinine clearance (mL/min) is calculated from serum creatinine by the following formulae:

CL CR (mL/min) = (140 u2013 age) x (Wt [kg]) x constant* S CR [u03bcmol/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 CL CR (mL/min) = (140 u2013 age) x (Wt [kg]) x 0,85 (if female) S CR [u03bcmol/L]

CL CR = creatinine clearance S CR = serum creatinine

Table 1 VALCYTE 450 film-coated tablet dose for renally impaired patients

CrCl (mL/min) Induction dose of VALCYTE 450 film-coated tablet Maintenance/Prevention dose of VALCYTE 450 film-coated tablet

u2265 60 900 mg twice daily 900 mg once daily

40 u2013 59 450 mg twice daily 450 mg once daily

25 u2013 39 450 mg once daily 225 mg once daily

10 u2013 24 450 mg every 2 days (tablets) 125 mg once daily

< 10 Not recommended Not recommended

Table 2 VALCYTE 50 mg/mL oral solution dose for renally impaired patients

CrCl (mL/min) Induction dose of VALCYTE 50 mg/mL oral solution Maintenance/Prevention dose of VALCYTE 50 mg/mL oral solution

u2265 60 900 mg twice daily 900 mg once daily

40 u2013 59 450 mg twice daily 450 mg once daily

25 u2013 39 225 mg once daily 225 mg once daily

10 u2013 24 200 mg (3 x weekly after dialysis) 125 mg once daily

< 10 Not recommended 100 mg (3 x weekly after dialysis)

Patients undergoing haemodialysis

Dosage adjustment is necessary for patients on haemodialysis (CrCl < 10 mL/min) and a dosing recommendation for VALCYTE 50 mg/mL Powder for oral solution is given in the above table.

Hepatic impairment

The safety and efficacy of VALCYTE have not been established in patients with hepatic impairment (see section 5.2).

VALCYTE is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any of the excipient.

Cross hypersensitivity

Due to the similarity of the chemical structure of VALCYTE and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these medicines is possible. Caution should therefore be used when prescribing VALCYTE to patients with known hypersensitivity to acyclovir or penciclovir, (or to their prodrugs, valaciclovir or famciclovir respectively).

Contraception

Prior to initiation of VALCYTE treatment, patients should be advised of the potential risks to the foetus and to use contraceptive measures (see section 4.6). Women of child bearing potential must use effective contraception during treatment. Male patients must practice barrier contraception during, and for at least 90 days following treatment with VALCYTE.

Myelosuppression

VALCYTE 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. Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anaemia have been observed in patients treated with VALCYTE (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/u03bcL, or the platelet count is less than 25 000/u03bcL, or the haemoglobin level is less than 8 g/dL. It is recommended that complete blood counts and platelet counts be monitored during therapy, particularly in patients with renal impairment and in neonates and infants (see section 4.8). In patients with severe leukopenia, neutropenia, anaemia and/or thrombocytopenia treatment with haematopoietic growth factors and/or interruption of therapy is recommended.

Safety and efficacy in children have not been established in adequate and well-controlled clinical studies. See section 4.2. The bioavailability of ganciclovir from VALCYTE is up to 10-fold higher than from ganciclovir capsules. VALCYTE cannot be substituted for ganciclovir capsules on a one-to-one basis. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of VALCYTE tablets. See section 4.2. In patients with impaired renal function, dosage adjustments based on creatinine clearance are required. See section 4.2. For patients on haemodialysis (CrCl < 10 mL/min) a tablet dose recommendation cannot be given. Thus VALCYTE 50 mg/mL Powder for oral solution, should be used in these patients.

Use with other medicines

Seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. VALCYTE should not be used concomitantly with imipenem-cilastatin unless the potential benefit outweighs the potential risks. See section 4.5. Zidovudine and VALCYTE each have the potential to 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 VALCYTE, 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 VALCYTE may result in added toxicity. See section 4.5. VALCYTE 50 mg/mL powder for oral solution contains 1 mg/mL sodium benzoate in each bottle. Benzoates cause mild irritation to the skin, eyes and mucous membranes. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old). VALCYTE 50 mg/mL powder for oral solution contains less than 1 mmol sodium (23 mg) per bottle, that is to say essentially u2018sodium-freeu2019.

Medicine interactions with VALCYTE

VALCYTE is the pro-drug of ganciclovir. Therefore, interactions associated with ganciclovir are expected.

Imipenem-cilastatin

Seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly and a pharmacodynamic interaction between these two medicines cannot be discounted. These medicines should not be used concomitantly unless the potential benefit outweighs the potential risks. See section 4.4.

Potential medicine interactions

Toxicity may be enhanced when ganciclovir/valganciclovir 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. This includes nucleoside analogues (e.g. zidovudine, didanosine, stavudine), immunosuppressants (e.g. ciclosporin, tacrolimus, mycophenolate mofetil), antineoplastic agents (e.g. doxorubicin, vinblastine, vincristine, hydroxyurea) and anti-infective agents (trimethoprim/sulphonamides, dapsone, amphotericin B, flucytosine, pentamidine). Therefore, these medicines should only be considered for concomitant use with VALCYTE only if the potential benefits outweigh the potential risks. See section 4.4.

Zidovudine

Both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, a pharmacodynamic interaction may occur during concomitant administration of these medicines, some patients may not tolerate concomitant therapy at full dosage. See section 4.4.

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with IV ganciclovir. 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 confirming a pharmacokinetic interaction during the concomitant administration of these medicines. There was no significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (e.g. pancreatitis). See section 4.4.

Probenecid

Probenecid given with oral ganciclovir resulted in statistically significant decreased renal clearance of ganciclovir (20 %) leading to statistically significantly increased exposure (40 %). These changes were consistent with a mechanism of interaction involving competition for renal tubular excretion. Therefore, patients taking probenecid and VALCYTE should be closely monitored for ganciclovir toxicity.

Contraception in males and females

Women of reproductive potential should use effective contraception during and for at least 30 days after treatment. Sexually active men should use condoms during and for at least 90 days after cessation of treatment with VALCYTE, unless it is certain that the female partner is not at risk of becoming pregnant (see section 4.4).

Pregnancy

In animal studies, ganciclovir was shown to be embryotoxic and was associated with reproductive toxicity and teratogenicity. The safety of VALCYTE in pregnant and lactating women has not been established. However, VALCYTE readily diffuses across the human placenta. The safe use of VALCYTE during labour and delivery has not been established.

Lactation

Women using VALCYTE should not breastfeed their infants. Peri- and postnatal development has not been studied with VALCYTE, but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the breast-fed infant cannot be discounted. Human data are not available but animal data indicates that ganciclovir is excreted in the milk of lactating rats.

Fertility

In animal studies ganciclovir was found to impair fertility. In a clinical study, renal transplant patients receiving VALCYTE for CMV prophylaxis for up to 200 days were compared to an untreated control group. Spermatogenesis was inhibited during treatment with VALCYTE. At follow-up, approximately six months after treatment discontinuation, the mean sperm density in treated patients was comparable to that observed in the untreated control group. In VALCYTE treated patients, all patients with normal sperm density (n = 7) and 8/13 patients with low sperm density at baseline, had normal density after treatment cessation. In the control group, all patients with normal sperm density (n = 6) and 2/4 patients with low sperm density at baseline, had normal density at the end of follow-up.

Adverse reactions such as seizures, dizziness and confusion have been reported with the use of VALCYTE and/or ganciclovir (see section 4.8). If they occur, such effects may affect tasks requiring alertness including the patientu2019s ability to drive and operate machinery.

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 VALCYTE administration.

a.) Summary of the safety profile

Clinical trials

All of the undesirable effects observed in VALCYTE clinical studies have been previously observed with ganciclovir. Therefore, adverse drug reactions reported with IV or oral ganciclovir (no longer available) or with VALCYTE are included in the table of adverse reactions (Table 3).

In patients treated with VALCYTE/ganciclovir the most serious and frequent adverse drug reactions are haematological reactions and include neutropenia, anaemia and thrombocytopenia. The frequencies presented in the table of adverse reactions are derived from a pooled population of patients (n = 1704) receiving maintenance therapy with ganciclovir (GAN 1697, GAN 1653, GAN 2304, GAN 1774, GAN 2226, AVI 034, GAN 041) or valganciclovir (WV15376, WV15705). Exception is made for anaphylactic reaction, agranulocytosis and granulocytopenia the frequencies of which are derived from post-marketing experience. Frequencies are presented as percentages and as CIOMS frequency categories defined as very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000) and very rare (< 1/10 000).

The overall safety profile of ganciclovir/VALCYTE is consistent in HIV and transplant populations except that retinal detachment has only been reported in patients with CMV retinitis. However, there are some differences in the frequency of certain reactions. VALCYTE is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. Pyrexia, candida infections, depression, severe neutropenia (ANC < 500/u03bcL) and skin reactions are reported more frequently in patients with HIV. Renal and hepatic dysfunction are reported more frequently in organ transplant recipients.

b.) Tabulated list of adverse drug reactions

Table 3 Frequency of Ganciclovir/Valganciclovir ADRs Reported in HIV Patients Receiving Maintenance Therapy (n=1704)

ADR (MedDRA) System Organ Class Percentage Frequency Category Infections and infestations: Candida infections including oral candidiasis. 22,42 % Very common Upper respiratory tract infection 16,26 % Sepsis 6,92 % Common Influenza 3,23 % Urinary tract infection 2,35 % Cellulitis 1,47 % Blood and lymphatic disorders: Neutropenia 26,12 % Very common Anaemia 19,89 % Thrombocytopenia 7,34 % Common Leukopenia 3,93 % Pancytopenia 1,06 % Bone marrow failure 0,29 % Uncommon Aplastic anaemia 0,06 % Rare Agranulocytosis* 0,02 % Granulocytopenia* 0,02 % Immune system disorders: Hypersensitivity 1,12 % Common Anaphylactic reaction* 0,02 % Rare Metabolic and nutrition disorders: Decreased appetite 12,09 % Very common Weight decreased 6,46 % Common Psychiatric disorders: Depression 6,69 % Common Confusional state 2,99 % Anxiety 2,64 % Agitation 0,59 % Uncommon Psychotic disorder 0,23 % Thinking abnormal 0,18 % Hallucinations 0,18 % Nervous system disorders: Headache 17,37 % Very common Insomnia 7,22 % Common Neuropathy peripheral 6,16 % Dizziness 5,52 % Paraesthesia 3,58 % Hypoaesthesia 2,58 % Seizures 2,29 % Dysgeusia (taste disturbance) 1,35 % Tremor 0,88 % Uncommon Eye disorders: Visual impairment 7,10 % Common Retinal detachment** 5,93 % Vitreous floaters 3,99 % Eye pain 2,99 % Conjunctivitis 1,58 % Macular oedema 1,06 % Ear and labyrinth disorders: Ear pain 1,17 % Common Deafness 0,65 % Uncommon Cardiac disorders: Dysrhythmia 0,47 % Uncommon Vascular disorders: Hypotension 2,05 % Common Respiratory, thoracic and mediastinal disorders: Cough 18,31 % Very common Dyspnea 11,80 % Gastrointestinal disorders: Diarrhoea 34,27 % Very common Nausea 26,35 % Vomiting 14,85 % Abdominal pain 10,97 % Dyspepsia 4,81 % Common Flatulence 4,58 % Abdominal pain upper 4,58 % Constipation 3,70 % Mouth ulceration 3,17 % Dysphagia 2,93 % Abdominal distention 2,41% Pancreatitis 1,64% Hepato-biliary disorders: Blood alkaline phosphatase increased 3,58 % Common Hepatic function abnormal 3,23 % Aspartate aminotransferase increased 1,88 % Alanine aminotransferase increased 1,23 % Skin and subcutaneous tissues disorders: Dermatitis 11,80 % Very common Night sweats 7,92 % Common Pruritus 4,58 % Rash 2,52 % Alopecia 1,29 % Dry skin 0,94 % Uncommon Urticaria 0,70 % Musculo-skeletal and connective tissue disorders: Back pain 4,46 % Common Myalgia 3,52 % Arthralgia 3,35 % Muscle spasms 2,99 % Renal and urinary disorders: Renal impairment 2,52 % Common Decreased renal creatinine clearance 2,35 % Serum creatinine increased 1,88 % Renal failure 0,76 % Uncommon Haematuria 0,70 % Reproductive system and breast disorders: Infertility male 0,23 % Uncommon General disorders and administration site conditions: Pyrexia 33,51 % Very common Fatigue 18,96 % Pain 5,81 % Common Chills 5,40 % Malaise 2,11 % Asthenia 2,00 % Chest pain 0,88 % Uncommon

It is expected that an overdose of VALCYTE, 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, elevated creatinine.
• Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting.
• Neurotoxicity: generalised tremors, seizures.

Haemodialysis and hydration may be of benefit in reducing valganciclovir and mainly ganciclovir blood plasma levels in patients who receive an overdose of VALCYTE.