Nyctos

Posology

Caution - Strict adherence to dosage recommendations is essential to avoid overdose.

Valganciclovir is rapidly and extensively metabolised to ganciclovir after oral dosing. Oral valganciclovir 900 mg taken twice daily is therapeutically equivalent to intravenous ganciclovir 5 mg/kg taken twice daily. The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is equivalent to valganciclovir 900 mg tablets.

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 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 once daily. 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 population

The safety and efficacy of Nyctos 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 once daily, starting within 10 days post-transplantation and continuing until 100 days post transplantation. Prophylaxis may be continued until 200 days post-transplantation.

For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg once daily, starting within 10 days post-transplantation and continuing until 100 days post-transplantation.

Paediatric population

In paediatric solid organ transplant patients, aged from birth, who are at risk of developing CMV disease, the recommended once daily dose of Nyctos 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/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation:

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.

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

*For appropriate sub-populations a lowering of k value may also be necessary (e.g. in paediatric patients with low birth weight).

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 (7x 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. 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, Nyctos film-coated 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 the prophylaxis period.

Special dosage instructions

Paediatric population

Dosing of paediatric SOT patients is individualised based on a patient's renal function, together with body surface area.

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, Nyctos should be administered to elderly patients with special consideration of their renal status (see table below).

Patients with renal impairment

Serum creatinine levels or estimated creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance, as shown in the Table below.

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

For females = 0.85 × male value

Patients undergoing haemodialysis:

Dosage adjustment is necessary for patients on haemodialysis (Clcr <10ml/min) and a dosing recommendation is given in the Table above.

Patients with hepatic impairment

Safety and efficacy of Nyctos have not been established in patients with hepatic impairment.

Patients with severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia:

Method of administration

Nyctos is administered orally, and whenever possible, should be taken with food.

Precautions to be taken before handling or administering the medicinal product

Nyctos powder for oral solution requires reconstitution prior to oral administration.6.

Caution - Strict adherence to dosage recommendations is essential to avoid overdose.

Nyctos is rapidly and extensively metabolised to ganciclovir after oral dosing. Oral Nyctos 900 mg twice daily is therapeutically equivalent to intravenous ganciclovir 5 mg/kg twice daily.

Posology

Treatment of cytomegalovirus (CMV) retinitis

Adult patients

Induction treatment of CMV retinitis:

For patients with active CMV retinitis, the recommended dose is 900 mg Nyctos (two Nyctos tablets) twice a day for 21 days and, whenever possible, 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 Nyctos (two Nyctos tablets) once daily and, whenever possible, taken with food. Patients whose retinitis worsens may repeat induction treatment; however, consideration should be given to the possibility of viral drug resistance.

Paediatric population

The safety and efficacy of Nyctos 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 (two Nyctos tablets) once daily, starting within 10 days post-transplantation and continuing until 100 days post-transplantation. Prophylaxis may be continued until 200 days post-transplantation.

For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg (two Nyctos tablets) once daily, starting within 10 days post-transplantation and continuing until 100 days post-transplantation.

Paediatric population

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

Paediatric Dose (mg) = 7 x BSA x CrCLS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below).

If the calculated Schwartz creatinine clearance exceeds 150 ml/min/1.73m², then a maximum value of 150 ml/min/1.73m² should be used in the equation:

Serum Creatinine (mg/dl)

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.

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

*For appropriate sub-populations a lowering of k value may also be necessary (e.g. in paediatric patients with low birth weight).

For paediatric kidney transplant patients, the recommended once daily mg dose (7 x BSA x CrCLS) 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 (7x BSA x CrCLS) 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. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. An oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Nyctos 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, 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 the prophylaxis period.

Special dosage instructions

Renal impairment

Serum creatinine levels or creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance, as shown in the table below.

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

For females = 0.85 x male value

Patients undergoing haemodialysis:

For patients on haemodialysis (CrCl < 10 ml/min) a dose recommendation cannot be given. Thus Nyctos should not be used in these patients.

Hepatic impairment:

The safety and efficacy of Nyctos has not been studied in patients with hepatic impairment.

Paediatric population:

Dosing of paediatric SOT patients is individualised based on a patient's renal function, together with body length and weight.

Elderly patients:

Safety and efficacy of Nyctos has not been established in this patient population.

Patients with severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia:

If there is a significant deterioration of blood cell counts during therapy with Nyctos, treatment with haematopoietic growth factors and/or dose interruption should be considered.

Method of administration

Nyctos tablets are administered orally, and whenever possible, should be taken with food.

For paediatric patients who are unable to swallow Nyctos tablets, other formulations, which may be available, should be used.

Precautions to be taken before handling or administering the medicinal product

The tablets should not be broken or crushed. Since Nyctos is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets. 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.

Posology

Caution - Strict adherence to dosage recommendations is essential to avoid overdose.

Valganciclovir is rapidly and extensively metabolised to ganciclovir after oral dosing. Oral valganciclovir 900 mg b.i.d. is therapeutically equivalent to intravenous ganciclovir 5 mg/kg b.i.d.

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 and, whenever possible, 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 900mg valganciclovir (two Valcyte 450 mg tablets) once daily and, whenever possible, 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 population

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 (two Valcyte 450 mg tablets) once daily, starting within 10 days post-transplantation and continuing until 100 days post-transplantation. Prophylaxis may be continued until 200 days post-transplantation.

For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg (two Valcyte 450 mg tablets) once daily, starting within 10 days post-transplantation and continuing until 100 days post-transplantation.

Whenever possible, the tablets should be taken with food.

Paediatric population

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/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation:

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.

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

*For appropriate sub-populations a lowering of k value may also be necessary (e.g. in paediatric patients with low birth weight).

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 (7x 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. 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 film-coated 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 the prophylaxis period.

Special dosage instructions

Paediatric population:

Dosing of paediatric SOT patients is individualised based on a patient's renal function, together with body surface area.

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 below).

Patients with renal impairment:

Serum creatinine levels or estimated creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance, as shown in the table below.

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

For females = 0.85 × male value

Patients undergoing haemodialysis:

For patients on haemodialysis (Clcr < 10 ml/min) a dose recommendation cannot be given. Thus Valcyte film-coated tablets should not be used in these patients.

Patients with hepatic impairment:

Safety and efficacy of Valcyte tablets have not been established in patients with hepatic impairment.

Patients with severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia:

If there is a significant deterioration of blood cell counts during therapy with Valcyte, treatment with haematopoietic growth factors and/or dose interruption should be considered.

Method of administration

Valcyte is administered orally, and whenever possible, should be taken with food.

For paediatric patients who are unable to swallow Valcyte film-coated tablets, Valcyte powder for oral solution can be administered.

Precautions to be taken before handling or administering the medicinal product

The tablets should not be broken or crushed. Since Valcyte is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets. 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.

Nyctos is contraindicated during breast-feeding.

Due to the similarity of the chemical structure of Nyctos and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these medicinal products is possible. Therefore, Nyctos is contraindicated in patients with hypersensitivity to aciclovir and valaciclovir.

Nyctos is contraindicated during breast-feeding.

Valcyte is contra-indicated during breast-feeding .

Cross-hypersensitivity

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

Precautions to be taken before handling

Owing to the teratogenic character, the Nyctos powder and reconstituted solution should be handled with caution. Inhalation should be avoided. If the powder or solution make direct contact with skin, the area should be washed thoroughly with soap and water. If the solution gets into the eye, the eye should be thoroughly washed with water immediately.

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception

Prior to the initiation of valganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies, ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and carcinogenic, and a suppressor of female fertility. Nyctos should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. It is also considered likely that Nyctos causes temporary or permanent inhibition of spermatogenesis. Women of child bearing potential must be advised to use effective contraception during and for at least 30 days after treatment. Men must be advised to practise barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy.

Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term.

Myelosuppression

Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anaemia have been observed in patients treated with Nyctos (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 level is less than 8g/dl.

When extending prophylaxis beyond 100 days the possible risk of developing leukopenia and neutropenia should be taken into account.

Nyctos should be used with caution in patients with pre-existing haematological cytopenia or a history of drug-related haematological cytopenia and in patients receiving radiotherapy.

It is recommended that complete blood counts and platelet counts should be monitored regularly during therapy. Increased haematological monitoring may be warranted in patients with renal impairment and paediatrics, at a minimum each time the patient attends the transplant clinic. In patients developing severe leukopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered.

Renal impairment

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.

Use with other medicines

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Nyctos should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks.

Patients treated with Nyctos and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity.

Controlled diet

For patients on a sodium-controlled diet, this medicinal product contains a total of 0.188 mg/ml sodium.

Prior to the initiation of Nyctos treatment, patients should be advised of the potential risks to the foetus. In animal studies, ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and carcinogenic, and a suppressor of female fertility. Nyctos should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. It is also considered likely that Nyctos causes temporary or permanent inhibition of spermatogenesis. Women of childbearing potential must be advised to use effective contraception during treatment. Men must be advised to practise barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy.

Nyctos has the potential to cause carcinogenicity and reproductive toxicity in the long term.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with Nyctos (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 level is less than 8 g/dl.

When extending prophylaxis beyond 100 days the possible risk of developing leucopenia and neutropenia should be taken into account.

Nyctos should be used with caution in patients with pre-existing haematological cytopenia or a history of drug-related haematological cytopenia and in patients receiving radiotherapy.

It is recommended that complete blood counts and platelet counts should be monitored regularly during therapy. Increased haematological monitoring may be warranted in patients with renal impairment and paediatrics, at a minimum each time the patient attends the transplant clinic. In patients developing severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered.

The bioavailability of ganciclovir after a single dose of 900 mg Nyctos is approximately 60 %, compared with approximately 6 % after administration of 1000 mg oral ganciclovir (as capsules). Excessive exposure to ganciclovir may be associated with life-threatening adverse reactions. Therefore, careful adherence to the dose recommendations is advised when instituting therapy, when switching from induction to maintenance therapy and in patients who may switch from oral ganciclovir to Nyctos as Nyctos 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 Nyctos tablets.

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.

Nyctos should not be used in patients on haemodialysis.

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Nyctos should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks.

Patients treated with Nyctos and (a) didanosine, (b) medicinal products that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity.

Cross-hypersensitivity

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

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception

Prior to the initiation of valganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies, ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and carcinogenic, and a suppressor of female fertility. Valcyte should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. It is also considered likely that Valcyte causes temporary or permanent inhibition of spermatogenesis. Women of child bearing potential must be advised to use effective contraception during and for at least 30 days after treatment. Men must be advised to practise barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy.

Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term.

Myelosuppression

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/μl, or the platelet count is less than 25000/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 taken into account.

Valcyte should be used with caution in patients with pre-existing haematological cytopenia or a history of drug-related haematological cytopenia and in patients receiving radiotherapy.

It is recommended that complete blood counts and platelet counts should be monitored regularly during therapy. Increased haematological monitoring may be warranted in patients with renal impairment and paediatrics, at a minimum each time the patient attends the transplant clinic. In patients developing severe leukopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered.

Difference in bioavailability with oral ganciclovir

The bioavailability of ganciclovir after a single dose of 900 mg valganciclovir is approximately 60 %, compared with approximately 6 % after administration of 1000 mg oral ganciclovir (as capsules). Excessive exposure to ganciclovir may be associated with life-threatening adverse reactions. Therefore, careful adherence to the dose recommendations is advised when instituting therapy, when switching from induction to maintenance therapy and in patients who may switch from oral ganciclovir to valganciclovir as 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.

Renal impairment

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.

Valcyte film-coated tablets should not be used in patients on haemodialysis.

Use with other medicines

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Valcyte should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks.

Patients treated with Valcyte and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity.

No studies on the effects on the ability to drive and use machines have been performed.

Convulsions, dizziness, a and confusion have been reported with the use of Nyctos and/or ganciclovir. If they occur, such effects may affect the patient's ability to drive and operate machinery.

No studies on the effects on ability to drive and use machines have been performed.

Convulsions, sedation, dizziness, ataxia, and/or confusion have been reported with the use of Nyctos and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness, including the patient's ability to drive and operate machinery.

No studies on the effects on ability to drive and use machines have been performed.

Convulsions, dizziness, and confusion have been reported with the use of Valcyte and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness, including the patient's ability to drive and operate machinery.

a Summary of the safety profile

Valganciclovir is a prodrug of ganciclovir, which is rapidly and extensively metabolised to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir use can be expected to occur with valganciclovir. All of the adverse drug reactions observed in valganciclovir clinical studies have been previously observed with ganciclovir. Therefore, adverse drug reactions reported with IV or oral ganciclovir (formulation no longer available) or with valganciclovir are included in the table of adverse drug reactions below.

The frequencies presented in the table of adverse reactions are derived from a pooled population of patients (n=1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exception is made for anaphylactic reaction, agranulocytosis and granulocytopenia, the frequencies of which are derived from post-marketing experience. Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000).

The overall safety profile of ganciclovir/valganciclovir 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. Valganciclovir is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. Pyrexia, candida infections, depression, severe neutropenia (ANC <500/μL) 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

*The frequencies of these adverse reactions are derived from post-marketing experience

**Retinal detachment has only been reported in AIDS patients treated for CMV retinitis

Description of selected adverse reactions

Neutropenia

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.

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 drugs are at greater risk of thrombocytopenia than patients with AIDS. 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 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 Nyctos 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.

c Paediatric population

Nyctos has been studied in 179 paediatric solid organ transplant patients who were at risk of developing CMV disease (aged 3 weeks to 16 years) and in 133 neonates with symptomatic congenital CMV disease (aged 2 to 31 days), with duration of ganciclovir exposure ranging from 2 to 200 days.

The most frequently reported adverse reactions on treatment in paediatric clinical trials were diarrhoea, nausea, neutropenia, leukopenia and anaemia.

In solid organ transplant patients, the overall safety profile was similar in paediatric patients as compared to adults. Neutropenia was reported with slightly higher incidence in the two studies conducted in paediatric solid organ transplant patients as compared to adults, but there was no correlation between neutropenia and infectious adverse events in the paediatric population.

In kidney transplant paediatric patients, prolongation of valganciclovir exposure up to 200 days was not associated with an overall increase in the incidence of adverse events. The incidence of severe neutropenia (ANC < 500/µL) was higher in paediatric kidney patients treated until Day 200 as compared to paediatric patients treated until Day 100 and as compared to adult kidney transplant patients treated until Day 100 or Day 200.

Only limited data are available in neonates or infants with symptomatic congenital CMV infection treated with Nyctos, however the safety appears to be consistent with the known safety profile of valganciclovir/ganciclovir.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

a. Summary of the safety profile

Nyctos is a prodrug of ganciclovir, which is rapidly and extensively metabolised to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir use can be expected to occur with Nyctos. All of the undesirable effects observed with Nyctos clinical studies have been previously observed with ganciclovir.

The most commonly reported adverse drug reactions following administration of Nyctos in adults are neutropenia, anaemia and diarrhoea.

Nyctos is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. In addition, Nyctos is associated with a higher risk of neutropenia and leucopenia compared to oral ganciclovir.

Severe neutropenia (ANC < 500 cells/μl) is seen more frequently in AIDS patients with CMV retinitis undergoing treatment with Nyctos than in solid organ transplant patients receiving Nyctos.

The frequency of adverse reactions reported in clinical trials with either Nyctos, oral ganciclovir, or intravenous ganciclovir is presented in the table below.

Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000).

The adverse reactions listed were reported in clinical trials in patients with AIDS for the induction or maintenance treatment of CMV retinitis, or in liver, kidney or heart transplant patients for the prophylaxis of CMV disease. The term (severe) in parenthesis in the table indicates that the adverse reaction has been reported in patients at both mild/moderate intensity and severe/life-threatening intensity at that specific frequency.

The overall safety profile of Nyctos did not change with the extension of prophylaxis up to 200 days in adult kidney transplant patients at high risk of CMV disease (D+/R-). Leucopenia 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.

b. Tabulated list of adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Severe thrombocytopenia may be associated with potentially life-threatening bleeding.

Retinal detachment has only been reported in AIDS patients treated with Nyctos for CMV retinitis.

c. Paediatric population

Nyctos has been studied in 179 paediatric solid organ transplant patients who were at risk of developing CMV disease (aged 3 weeks to 16 years) and in 133 neonates with symptomatic congenital CMV disease (aged 2 to 31 days), with duration of ganciclovir exposure ranging from 2 to 200 days.

The most frequently reported adverse reactions on treatment in paediatric clinical trials were diarrhoea, nausea, neutropenia, leucopenia and anaemia.

In solid organ transplant patients, the overall safety profile was similar in paediatric patients as compared to adults. However, the rates of certain adverse events, such as upper respiratory tract infection, pyrexia, abdominal pain and dysuria, which may be characteristic of the paediatric population, were reported in higher incidence in paediatrics than in adults. Neutropenia was also reported with slightly higher incidence in the two studies conducted in paediatric solid organ transplant patients as compared to adults, but there was no correlation between neutropenia and infectious adverse events in the paediatric population.

In kidney transplant paediatric patients, prolongation of Nyctos exposure up to 200 days was not associated with an overall increase in the incidence of adverse events. The incidence of severe neutropenia (ANC < 500/µl) was higher in paediatric kidney patients treated until Day 200 as compared to paediatric patients treated until Day 100 and as compared to adult kidney transplant patients treated until Day 100 or Day 200.

Only limited data are available in neonates or infants with symptomatic congenital CMV infection treated with Nyctos, however the safety appears to be consistent with the known safety profile of Nyctos/ganciclovir.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

a Summary of the safety profile

Valganciclovir is a prodrug of ganciclovir, which is rapidly and extensively metabolised to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir use can be expected to occur with valganciclovir. All of the adverse drug reactions observed in valganciclovir clinical studies have been previously observed with ganciclovir. Therefore, adverse drug reactions reported with IV or oral ganciclovir (formulation no longer available) or with valganciclovir are included in the table of adverse drug reactions below.

.

The frequencies presented in the table of adverse reactions are derived from a pooled population of patients (n=1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exception is made for anaphylactic reaction, agranulocytosis and granulocytopenia, the frequencies of which are derived from post-marketing experience. Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000).

The overall safety profile of ganciclovir/valganciclovir 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. Valganciclovir is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. Pyrexia, candida infections, depression, severe neutropenia (ANC <500/μL) 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

*The frequencies of these adverse reactions are derived from post-marketing experience

**Retinal detachment has only been reported in AIDS patients treated for CMV retinitis

Description of selected adverse reactions

Neutropenia

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.

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 drugs are at greater risk of thrombocytopenia than patients with AIDS. 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 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 Valcyte 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.

c Paediatric population

Valcyte has been studied in 179 paediatric solid organ transplant patients who were at risk of developing CMV disease (aged 3 weeks to 16 years) and in 133 neonates with symptomatic congenital CMV disease (aged 2 to 31 days), with duration of ganciclovir exposure ranging from 2 to 200 days.

The most frequently reported adverse reactions on treatment in paediatric clinical trials were diarrhoea, nausea, neutropenia, leukopenia and anaemia.

In solid organ transplant patients, the overall safety profile was similar in paediatric patients as compared to adults. Neutropenia was reported with slightly higher incidence in the two studies conducted in paediatric solid organ transplant patients as compared to adults, but there was no correlation between neutropenia and infectious adverse events in the paediatric population.

In kidney transplant paediatric patients, prolongation of valganciclovir exposure up to 200 days was not associated with an overall increase in the incidence of adverse events. The incidence of severe neutropenia (ANC < 500/µL) was higher in paediatric kidney patients treated until Day 200 as compared to paediatric patients treated until Day 100 and as compared to adult kidney transplant patients treated until Day 100 or Day 200.

Only limited data are available in neonates or infants with symptomatic congenital CMV infection treated with Valcyte, however the safety appears to be consistent with the known safety profile of valganciclovir/ganciclovir.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose experience with valganciclovir and intravenous ganciclovir

It is expected that an overdose of valganciclovir could possibly result in increased renal toxicity.

Reports of overdoses with intravenous ganciclovir, some with fatal outcomes, have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

Haematological toxicity: myelosuppression including pancytopenia, 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 tremor, convulsion

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

Symptoms

Overdose experience with Nyctos

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's degree of renal impairment (decreased creatinine clearance).

It is expected that an overdose of Nyctos could also possibly result in increased renal toxicity.

Overdose experience with intravenous ganciclovir

Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

- Haematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leucopenia, 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 tremor, convulsion.

Management

Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of Nyctos.

Overdose experience with valganciclovir and intravenous ganciclovir

It is expected that an overdose of valganciclovir could possibly result in increased renal toxicity.

Reports of overdoses with intravenous ganciclovir, some with fatal outcomes, have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

- Haematological toxicity: myelosuppression including pancytopenia, 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 tremor, convulsion.

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

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. 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).

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 intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

Antiviral Activity

The in-vitro anti-viral activity, measured as IC₅₀ of ganciclovir against CMV, is in the range of 0.08μM (0.02μg/ml) to 14μM (3.5μg/ml).

The clinical antiviral effect of Nyctos has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46% (32/69) of patients at study entry to 7% (4/55) of patients following four weeks of Nyctos treatment.

Clinical efficacy and safety

Adult patients

Treatment of CMV retinitis:

Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either Nyctos 900 mg (twice daily) or intravenous ganciclovir 5 mg/kg (twice daily). The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and valganciclovir arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with Nyctos given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with Nyctos was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Nyctos was 219 (125) days.

Prevention of CMV disease in transplantation

A double-blind, double-dummy clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastro-intestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either Nyctos (900 mg once daily) or oral ganciclovir (1000 mg three times daily) starting within 10 days of transplantation until Day 100 post-transplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first 6 months post-transplant was 12.1% in the Nyctos arm (n=239) compared with 15.2% in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7% in patients randomised to valganciclovir compared with 36.0% in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8% of patients, in each arm.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Nyctos CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Nyctos tablets (900 mg od) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease¹, 12 Month ITT Population ^A

¹ CMV Disease is defined as either CMV syndrome or tissue invasive CMV. ² Confirmed CMV is a clinically confirmed case of CMV disease. Patients were assumed to have CMV disease if there was no week 52 assessment and no confirmation of CMV disease before this time point.

^A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Nyctos until Day 200 post-transplant compared to patients who received CMV prophylaxis with Nyctos until Day 100 post-transplant.

The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.2% (160/163) for the 100 day dosing regimen and 98.1% (152/155) for the 200 day dosing regimen. Up to 24 month post-transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post-transplant, one additional case has been reported in the 200 days dosing group.

Viral Resistance

Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). In clinical isolates, seven canonical UL97 substitutions, M460V/I, H520Q, C592G, A594V, L595S, C603W are the most frequently reported ganciclovir resistance-associated substitutions. Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:

Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2%, 6.5%, 12.8%, and 15.3% contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV disease in transplantation:

Active comparator study

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9%) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9%.

Extending prophylaxis study from 100 to 200 days post-transplant

Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (>600 copies/ml) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.

Paediatric population

Treatment of CMV retinitis:

Prevention of CMV disease in transplantation

A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving valganciclovir once daily for up to 100 days according to the paediatric dosing algorithm produced exposures similar to that in adults. Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults.

A phase IV tolerability study in paediatric kidney transplant recipients (aged 1 to 16 years, n=57) receiving valganciclovir once daily for up to 200 days according to the dosing algorithm resulted in a low incidence of CMV. Follow up after treatment was 24 weeks. CMV D/R serology status at baseline was D+/R+ in 45%, D+/R- in 39%, D-/R+ in 7%, D-/R- in 7% and ND/R+ in 2% of the cases. CMV viremia was reported in 3 patients and a case of CMV syndrome was suspected in one patient but not confirmed by CMV PCR by the central laboratory. The observed adverse drug reactions were of similar nature to those in adults.

These data support the extrapolation of efficacy data from adults to children and provide posology recommendations for paediatric patients.

A phase I pharmacokinetic and safety study in heart transplant patients (aged 3 weeks to 125 days, n=14) who received a single daily dose of valganciclovir according to the paediatric dosing algorithm on 2 consecutive days produced exposures similar to those in adults. Follow up after treatment was 7 days. The safety profile was consistent with other paediatric and adult studies, although patient numbers and valganciclovir exposure were limited in this study.

Congenital CMV

The efficacy and safety of ganciclovir and/or valganciclovir was studied in neonates and infants with congenital symptomatic CMV infection in two studies.

In the first study, the pharmacokinetics and safety of a single dose of valganciclovir (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8 to34 days) with symptomatic congenital CMV disease. The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral valganciclovir, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for most of the study period. In the second study the efficacy and safety of six weeks versus six months of valganciclovir treatment was studied in 109 infants aged 2- to 30 days with symptomatic congenital CMV disease. All infants received oral valganciclovir at a dose of 16 mg/kg b.i.d. for 6 weeks. After 6 weeks of treatment the infants were randomized 1:1 to continue treatment with valganciclovir at the same dose or receive a matched placebo to complete 6 months of treatment.

This treatment indication is not currently recommended for valganciclovir. The design of the studies and results obtained are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

Pharmacotherapeutic group: Antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B14

Mechanism of action

Nyctos is an L-valyl ester (prodrug) of ganciclovir. After oral administration, Nyctos 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. 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, HHV8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).

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 intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

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).

The clinical antiviral effect of Nyctos has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46 % (32/69) of patients at study entry to 7 % (4/55) of patients following four weeks of Nyctos treatment.

Clinical efficacy and safety

Adult patients

Treatment of CMV retinitis:

Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either Nyctos 900 mg (twice daily) or intravenous ganciclovir 5 mg/kg (twice daily). The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and Nyctos arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with Nyctos given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with Nyctos was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Nyctos was 219 (125) days.

Prevention of CMV disease in transplantation:

A double-blind, double-dummy clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastrointestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either Nyctos (900 mg once daily) or oral ganciclovir (1000 mg three times daily) starting within 10 days of transplantation until Day 100 post-transplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first 6 months post-transplant was 12.1 % in the Nyctos arm (n=239) compared with 15.2 % in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the Nyctos arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7 % in patients randomised to Nyctos compared with 36.0 % in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8 % of patients, in each arm.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Nyctos CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomised (1:1) to receive Nyctos tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo.

The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease¹, 12 Month ITT Population^A

¹ CMV Disease is defined as either CMV syndrome or tissue invasive CMV.

² Confirmed CMV is a clinically confirmed case of CMV disease. Patients were assumed to have CMV disease if there was no week 52 assessment and no confirmation of CMV disease before this time point.

^A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Nyctos until Day 200 post-transplant compared to patients who received CMV prophylaxis with Nyctos until Day 100 post-transplant.

The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.2 % (160/163) for the 100 day dosing regimen and 98.1 % (152/155) for the 200 day dosing regimen. Up to 24 month post-transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post-transplant, one additional case has been reported in the 200 days dosing group.

Viral resistance

Virus resistant to ganciclovir can arise after chronic dosing with Nyctos by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). In clinical isolates, seven canonical UL97 substitutions, M460V/I, H520Q, C592G, A594V, L595S, C603W are the most frequently reported ganciclovir resistance-associated substitutions. Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:

Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2 %, 6.5 %, 12.8 %, and 15.3 % contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of Nyctos treatment.

Prevention of CMV disease in transplantation:

Active comparator study

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive Nyctos, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9 %) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive Nyctos, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9 %.

Extending prophylaxis study from 100 to 200 days post-transplant

Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (>600 copies/ml) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.

Paediatric population

Treatment of CMV retinitis:

Prevention of CMV disease in transplantation

A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving Nyctos once daily for up to 100 days according to the paediatric dosing algorithm produced exposures similar to that in adults. Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults.

A phase IV tolerability study in paediatric kidney transplant recipients (aged 1 to 16 years, n=57) receiving Nyctos once daily for up to 200 days according to the dosing algorithm resulted in a low incidence of CMV. Follow up after treatment was 24 weeks. CMV D/R serology status at baseline was D+/R+ in 45%, D+/R- in 39%, D-/R+ in 7%, D-/R- in 7% and ND/R+ in 2% of the cases. CMV viremia was reported in 3 patients and a case of CMV syndrome was suspected in one patient but not confirmed by CMV PCR by the central laboratory. The observed adverse drug reactions were of similar nature to those in adults.

These data support the extrapolation of efficacy data from adults to children and provide posology recommendations for paediatric patients.

A phase I pharmacokinetic and safety study in heart transplant patients (aged 3 weeks to 125 days, n=14) who received a single daily dose of Nyctos according to the paediatric dosing algorithm on 2 consecutive days produced exposures similar to those in adults. Follow up after treatment was 7 days. The safety profile was consistent with other paediatric and adult studies, although patient numbers and Nyctos exposure were limited in this study.

Congenital CMV

The efficacy and safety of ganciclovir and/or Nyctos was studied in neonates and infants with congenital symptomatic CMV infection in two studies.

In the first study, the pharmacokinetics and safety of a single dose of Nyctos (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8 to 34 days) with symptomatic congenital CMV disease. The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral Nyctos, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for the most time of the study period. In the second study the efficacy and safety of six weeks versus six months of Nyctos treatment was studied in 109 infants aged 2 to 30 days with symptomatic congenital CMV disease. All infants received oral Nyctos at a dose of 16 mg/kg twice daily for 6 weeks. After 6 weeks of treatment the infants were randomised 1:1 to continue treatment with Nyctos at the same dose or receive a matched placebo to complete 6 months of treatment.

This treatment indication is not currently recommended for Nyctos. The design of the studies and results obtained are too limited to allow appropriate efficacy and safety conclusions on Nyctos.

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. 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, HHV8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).

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 intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

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).

The clinical antiviral effect of Valcyte has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46 % (32/69) of patients at study entry to 7 % (4/55) of patients following four weeks of Valcyte treatment.

Clinical efficacy and safety

Adult patients

Treatment of CMV retinitis:

Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either Valcyte 900 mg b.i.d or intravenous ganciclovir 5 mg/kg b.i.d. The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and valganciclovir arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with Valcyte given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with Valcyte was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Valcyte was 219 (125) days.

Prevention of CMV disease in transplantation:

A double-blind, double-dummy, clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastro-intestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either Valcyte (900 mg od) or oral ganciclovir (1000 mg t.i.d.) starting within 10 days of transplantation until Day 100 post-transplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first 6 months post-transplant was 12.1 % in the Valcyte arm (n=239) compared with 15.2 % in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7 % in patients randomised to valganciclovir compared with 36.0 % in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8 % of patients, in each arm.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg od) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo.

The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease¹, 12 Month ITT Population ^A

¹ CMV Disease is defined as either CMV syndrome or tissue invasive CMV. ² Confirmed CMV is a clinically confirmed case of CMV disease. Patients were assumed to have CMV disease if there was no week 52 assessment and no confirmation of CMV disease before this time point.

^A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Valcyte until Day 200 post-transplant compared to patients who received CMV prophylaxis with Valcyte until Day 100 post-transplant.

The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.2 % (160/163) for the 100 day dosing regimen and 98.1 % (152/155) for the 200 day dosing regimen. Up to 24 month post-transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post-transplant, one additional case has been reported in the 200 days dosing group.

Viral resistance

Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). In clinical isolates, seven canonical UL97 substitutions, M460V/I, H520Q, C592G, A594V, L595S, C603W are the most frequently reported ganciclovir resistance-associated substitutions. Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:

Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2 %, 6.5 %, 12.8 %, and 15.3 % contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV disease in transplantation:

Active comparator study

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9 %) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9 %.

Extending prophylaxis study from 100 to 200 days post-transplant

Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (> 600 copies/ml) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.

Paediatric population

Treatment of CMV retinitis:

Prevention of CMV disease in transplantation

A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving valganciclovir once daily for up to 100 days according to the paediatric dosing algorithm produced exposures similar to that in adults. Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults.

A phase IV tolerability study in paediatric kidney transplant recipients (aged 1 to 16 years, n=57) receiving valganciclovir once daily for up to 200 days according to the dosing algorithm resulted in a low incidence of CMV. Follow up after treatment was 24 weeks. CMV D/R serology status at baseline was D+/R+ in 45%, D+/R- in 39%, D-/R+ in 7%, D-/R- in 7% and ND/R+ in 2% of the cases. CMV viremia was reported in 3 patients and a case of CMV syndrome was suspected in one patient but not confirmed by CMV PCR by the central laboratory. The observed adverse drug reactions were of similar nature to those in adults.

These data support the extrapolation of efficacy data from adults to children and provide posology recommendations for paediatric patients.

A phase I pharmacokinetic and safety study in heart transplant patients (aged 3 weeks to 125 days, n=14) who received a single daily dose of valganciclovir according to the paediatric dosing algorithm on 2 consecutive days produced exposures similar to those in adults. Follow up after treatment was 7 days. The safety profile was consistent with other paediatric and adult studies, although patient numbers and valganciclovir exposure were limited in this study.

Congenital CMV

The efficacy and safety of ganciclovir and/or valganciclovir was studied in neonates and infants with congenital symptomatic CMV infection in two studies.

In the first study, the pharmacokinetics and safety of a single dose of valganciclovir (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8 to 34 days) with symptomatic congenital CMV disease. The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral valganciclovir, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for the most time of the study period. In the second study the efficacy and safety of six weeks versus six months of valganciclovir treatment was studied in 109 infants aged 2 to 30 days with symptomatic congenital CMV disease. All infants received oral valganciclovir at a dose of 16 mg/kg b.i.d. for 6 weeks. After 6 weeks of treatment the infants were randomized 1:1 to continue treatment with valganciclovir at the same dose or receive a matched placebo to complete 6 months of treatment.

This treatment indication is not currently recommended for valganciclovir. The design of the studies and results obtained are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions.

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. Systemic exposure to valganciclovir is transient and low. The bioavailability of ganciclovir from oral dosing of valganciclovir is approximately 60% across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below).

Valganciclovir in HIV positive, CMV positive patients:

Systemic exposure of HIV positive, CMV positive patients after twice daily administration of ganciclovir and valganciclovir for one week is:

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:

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 effect:

When valganciclovir was given with food at the recommended dose of 900 mg, higher values were seen in both mean ganciclovir AUC (approximately 30%) and mean ganciclovir C_max values (approximately 14%) than in the fasting state. Also, the inter-individual variation in exposure of ganciclovir decreases when taking Nyctos with food. Nyctos has only been administered with food in clinical studies. Therefore, it is recommended that Nyctos be administered with food.

Distribution:

Because of rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined. The steady state volume of distribution (V_d) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114). For IV ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.54-0.87 L/kg. Ganciclovir penetrates the cerebrospinal fluid. Binding to plasma proteins was 1%-2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Biotransformation

Valganciclovir is rapidly and extensively metabolised to ganciclovir; no other metabolites have been detected. Ganciclovir itself is not metabolised to a significant extent.

Elimination

Following dosing with oral valganciclovir, the drug is rapidly hydrolysed to ganciclovir. Ganciclovir is eliminated from the systemic circulation by glomerular filtration and active tubular secretion. The half-life of ganciclovir from valganciclovir is 4.1 ± 0.9 hours in HIV- and CMV-seropositive patients. In patients with normal renal function greater than 90% of IV administered ganciclovir was recovered un-metabolized in the urine within 24 hours. In patients with normal renal function the post-peak plasma concentrations of ganciclovir after administration of valganciclovir decline with a half-life ranging from 0.4 h to 2.0 h.

Pharmacokinetics in special clinical situations

Paediatric population

In a phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) valganciclovir was given once daily for up to 100 days. Pharmacokinetic parameters were similar across organ type and age range and comparable with adults. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function.

In a phase I pharmacokinetic and safety study in paediatric heart transplant recipients (aged 3 weeks to 125 days, n = 14), valganciclovir was given once daily for two study days. Population pharmacokinetics estimated that mean bioavailability was 64%.

A comparison of the results from these two studies and the pharmacokinetic results from the adult population shows that ranges of AUC _0-24h were very similar across all age groups, including adults. Mean values for AUC_0-24h and C_max were also similar across the paediatric age groups < 12 years old, although there was a trend of decreasing mean values for AUC_0-24h and C_max across the entire pediatric age range, which appeared to correlate with increasing age. This trend was more apparent for mean values of clearance and half-life (t_1/2); however this is to be expected as clearance is influenced by changes in weight, height and renal function associated with patient growth, as indicated by population pharmacokinetic modelling.

The following table summarizes the model-estimated AUC_0-24h ranges for ganciclovir from these two studies, as well as mean and standard deviation values for AUC_0-24h, C_max, CL and t ½ for the relevant paediatric age groups compared to adult data:

* Extracted from study report PV 16000

Ganciclovir pharmacokinetics following valganciclovir administration were also evaluated in two studies in neonates and infants with symptomatic congenital CMV disease. In the first study 24 neonates aged 8 to 34 days received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral valganciclovir, where the dose of valganciclovir powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily; total treatment duration was 6 weeks. A dose of 16 mg/kg twice daily of valganciclovir powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose.

In the second study, 109 neonates aged 2 to 30 days received 16 mg/kg valganciclovir powder for oral solution twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomized to continue receiving valganciclovir or placebo for 6 months. However, the mean AUC_0-12h was lower compared to the mean AUC_0-12h values from the first study. The following table shows the mean values of AUC, C_max, and t_½ including standard deviations compared with adult data:

GAN = Ganciclovir, i.v. VAL = Valganciclovir, oral

These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients with congenital CMV infection.

Elderly

No investigations on valganciclovir or ganciclovir pharmacokinetics in adults older than 65 years of age have been undertaken.

Patients with renal impairment

The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir was evaluated in 24 otherwise healthy individuals with renal impairment.

Pharmacokinetic parameters of ganciclovir from a single oral dose of 900 mg Nyctos tablets in patients with various degrees of renal impairment:

Decreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients.

Patients undergoing haemodialysis

For patients receiving haemodialysis Nyctos powder for oral solution is recommended to provide an individualised dose.

Stable liver transplant patients

The pharmacokinetics of ganciclovir from valganciclovir in stable liver transplant patients were investigated in one open label 4-part crossover study (N=28). The bioavailability of ganciclovir from valganciclovir, following a single dose of 900 mg valganciclovir under fed conditions, was approximately 60%. Ganciclovir AUC_0-24h was comparable to that achieved by 5 mg/kg intravenous ganciclovir in liver transplant patients.

Patients with hepatic impairment

The safety and efficacy of Nyctos have not been studied in patients with hepatic impairment. Hepatic impairment should not significantly affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made.

Patients with cystic fibrosis

In a phase I pharmacokinetic study in lung transplant recipients with or without cystic fibrosis (CF), 31 patients (16 CF/15 non-CF) received post-transplant prophylaxis with 900 mg/day Nyctos. The study indicated that cystic fibrosis had no statistically significant influence on the overall average systemic exposure to ganciclovir in lung transplant recipients. Ganciclovir exposure in lung transplant recipients was comparable to that shown to be efficacious in the prevention of CMV disease in other solid organ transplant recipients.

The pharmacokinetic properties of Nyctos have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Absorption

Nyctos 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. Systemic exposure to Nyctos is transient and low. The bioavailability of ganciclovir from oral dosing of Nyctos is approximately 60 % across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below). For comparison, the bioavailability of ganciclovir after administration of 1000 mg oral ganciclovir (as capsule) is 6-8%.

Nyctos in HIV positive, CMV positive patients:

Systemic exposure of HIV positive, CMV positive patients after twice daily administration of ganciclovir and Nyctos for one week is:

The efficacy of ganciclovir in increasing the time-to-progression of CMV retinitis has been shown to correlate with systemic exposure (AUC).

Nyctos in solid organ transplant patients:

Steady state systemic exposure of solid organ transplant patients to ganciclovir after daily oral administration of ganciclovir and Nyctos is:

The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar after oral administration of Nyctos according to the renal function dosing algorithm.

Food effect:

Dose proportionality with respect to ganciclovir AUC following administration of Nyctos in the dose range 450 to 2625 mg was demonstrated only under fed conditions. When Nyctos was given with food at the recommended dose of 900 mg, higher values were seen in both mean ganciclovir AUC (approximately 30 %) and mean ganciclovir C_max values (approximately 14 %) than in the fasting state. Also, the inter-individual variation in exposure of ganciclovir decreases when taking Nyctos with food. Nyctos has only been administered with food in clinical studies. Therefore, it is recommended that Nyctos be administered with food.

Distribution

Because of rapid conversion of Nyctos to ganciclovir, protein binding of Nyctos was not determined. Plasma protein binding of ganciclovir was 1 - 2 % over concentrations of 0.5 and 51 μg/ml. The steady state volume of distribution (V_d) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114).

Biotransformation

Nyctos is rapidly and extensively metabolised to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabelled ganciclovir (1000 mg single dose) accounted for more than 1 - 2 % of the radioactivity recovered in the faeces or urine.

Elimination

Following dosing with Nyctos, renal excretion, as ganciclovir, by glomerular filtration and active tubular secretion is the major route of elimination of Nyctos. Renal clearance accounts for 81.5 % ± 22 % (n=70) of the systemic clearance of ganciclovir. Post-hoc Bayesian estimates for population mean apparent clearance of ganciclovir in patients with CrCl > 60 ml/min is 14.05 ± 4.13 l/h. In patients with renal impairment, the mean apparent clearance of ganciclovir is 8.46 ± 1.67 l/h (CrCl between 40 and 60 ml/min) and 7.00 ± 1.08 l/h (CrCl between 25 and 40 ml/min).The half-life of ganciclovir from Nyctos is 4.1 ± 0.9 hours in HIV- and CMV-seropositive patients.

Pharmacokinetics in special clinical situations

Patients with renal impairment

Decreasing renal function resulted in decreased clearance of ganciclovir from Nyctos with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients.

Patients undergoing haemodialysis

For patients receiving haemodialysis dose recommendations for Nyctos tablets cannot be given. This is because an individual dose of Nyctos required for these patients is less than the 450 mg tablet strength. Thus, Nyctos film-coated tablets should not be used in these patients.

Patients with hepatic impairment

The safety and efficacy of Nyctos have not been studied in patients with hepatic impairment. Hepatic impairment should not affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made.

Patients with cystic fibrosis

In a phase I pharmacokinetic study in lung transplant recipients with or without cystic fibrosis (CF), 31 patients (16 CF/15 non-CF) received post-transplant prophylaxis with 900 mg/day Nyctos. The study indicated that cystic fibrosis had no statistically significant influence on the overall average systemic exposure to ganciclovir in lung transplant recipients. Ganciclovir exposure in lung transplant recipients was comparable to that shown to be efficacious in the prevention of CMV disease in other solid organ transplant recipients.

Paediatric population

In a phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) Nyctos was given once daily for up to 100 days. Pharmacokinetic parameters were similar across organ type and age range and comparable with adults. Population pharmacokinetic modelling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function.

In a phase I pharmacokinetic and safety study in paediatric heart transplant recipients (aged 3 weeks to 125 days, n = 14), Nyctos was given once daily for two study days. Population pharmacokinetics estimated that mean bioavailability was 64%.

A comparison of the results from these two studies and the pharmacokinetic results from the adult population shows that ranges of AUC_0-24h were very similar across all age groups, including adults. Mean values for AUC_0-24h and C_max were also similar across the paediatric age groups < 12 years old, although there was a trend of decreasing mean values for AUC_0-24h and C_max across the entire paediatric age range, which appeared to correlate with increasing age. This trend was more apparent for mean values of clearance and half-life (t_1/2); however this is to be expected as clearance is influenced by changes in weight, height and renal function associated with patient growth, as indicated by population pharmacokinetic modelling.

The following table summarises the model-estimated AUC_0-24h ranges for ganciclovir from these two studies, as well as mean and standard deviation values for C_max, t ½, CL and AUC_0-24h for the relevant paediatric age groups compared to adult data:

* Extracted from study report PV 16000

Ganciclovir pharmacokinetics following Nyctos administration were also evaluated in two studies in neonates and infants with symptomatic congenital CMV disease. In the first study 24 neonates aged 8 to 34 days received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral Nyctos, where the dose of Nyctos powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily; total treatment duration was 6 weeks. A dose of 16 mg/kg twice daily of Nyctos powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose.

In the second study, 109 neonates aged 2 to 30 days received 16 mg/kg Nyctos powder for oral solution twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomised to continue receiving Nyctos or placebo for 6 months. However, the mean AUC_0-12h was lower compared to the mean AUC_0-12h values from the first study. The following table shows the mean values of AUC, C_max, and t_½ including standard deviations compared with adult data:

GAN = Ganciclovir, i.v.

VAL = Nyctos, oral

These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients with congenital CMV infection.

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions.

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. Systemic exposure to valganciclovir is transient and low. The bioavailability of ganciclovir from oral dosing of valganciclovir is approximately 60 % across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below). For comparison, the bioavailability of ganciclovir after administration of 1000 mg oral ganciclovir (as capsules) is 6 - 8 %.

Valganciclovir in HIV positive, CMV positive patients:

Systemic exposure of HIV positive , CMV positive patients after twice daily administration of ganciclovir and valganciclovir for one week is:

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:

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.

Food effect:

When valganciclovir was given with food at the recommended dose of 900 mg, higher values were seen in both mean ganciclovir AUC (approximately 30 %) and mean ganciclovir C_max values (approximately 14 %) than in the fasting state. Also, the inter-individual variation in exposure of ganciclovir decreases when taking Valcyte with food. Valcyte has only been administered with food in clinical studies. Therefore, it is recommended that Valcyte be administered with food.

Distribution:

Because of rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined. The steady state volume of distribution (V_d) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114). For IV ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.54-0.87 L/kg. Ganciclovir penetrates the cerebrospinal fluid. Binding to plasma proteins was 1%-2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Biotransformation

Valganciclovir is rapidly and extensively metabolised to ganciclovir; no other metabolites have been detected. Ganciclovir itself is not metabolised to a significant extent.

Elimination

Following dosing with oral valganciclovir, the drug is rapidly hydrolysed to ganciclovir. Ganciclovir is eliminated from the systemic circulation by glomerular filtration and active tubular secretion. In patients with normal renal function greater than 90% of IV administered ganciclovir was recovered un-metabolized in the urine within 24 hours. In patients with normal renal function the post-peak plasma concentrations of ganciclovir after administration of valganciclovir decline with a half-life ranging from 0.4 h to 2.0 h.

Pharmacokinetics in special clinical situations

Paediatric population

In a phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) valganciclovir was given once daily for up to 100 days. Pharmacokinetic parameters were similar across organ type and age range and comparable with adults. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function.

In a phase I pharmacokinetic and safety study in paediatric heart transplant recipients (aged 3 weeks to 125 days, n = 14), valganciclovir was given once daily for two study days. Population pharmacokinetics estimated that mean bioavailability was 64%.

A comparison of the results from these two studies and the pharmacokinetic results from the adult population shows that ranges of AUC _0-24h were very similar across all age groups, including adults. Mean values for AUC_0-24h and C_max were also similar across the paediatric age groups < 12 years old, although there was a trend of decreasing mean values for AUC_0-24h and C_max across the entire pediatric age range, which appeared to correlate with increasing age. This trend was more apparent for mean values of clearance and half-life (t_1/2); however this is to be expected as clearance is influenced by changes in weight, height and renal function associated with patient growth, as indicated by population pharmacokinetic modelling.

The following table summarizes the model-estimated AUC_0-24h ranges for ganciclovir from these two studies, as well as mean and standard deviation values for AUC_0-24h, C_max, CL and t ½ for the relevant paediatric age groups compared to adult data:

* Extracted from study report PV 16000

Ganciclovir pharmacokinetics following valganciclovir administration were also evaluated in two studies in neonates and infants with symptomatic congenital CMV disease. In the first study 24 neonates aged 8 to 34 days received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral valganciclovir, where the dose of valganciclovir powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily; total treatment duration was 6 weeks. A dose of 16 mg/kg twice daily of valganciclovir powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose.

In the second study, 109 neonates aged 2 to 30 days received 16 mg/kg valganciclovir powder for oral solution twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomized to continue receiving valganciclovir or placebo for 6 months. However, the mean AUC_0-12h was lower compared to the mean AUC_0-12h values from the first study. The following table shows the mean values of AUC, C_max, and t_½ including standard deviations compared with adult data:

GAN = Ganciclovir, i.v. VAL = Valganciclovir, oral

These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients with congenital CMV infection.

Elderly

No investigations on valganciclovir or ganciclovir pharmacokinetics in adults older than 65 years of age have been undertaken.

Patients with renal impairment

The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir was evaluated in 24 otherwise healthy individuals with renal impairment.

Pharmacokinetic parameters of ganciclovir from a single oral dose of 900 mg Valcyte tablets in patients with various degrees of renal impairment:

Decreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients.

Patients undergoing haemodialysis

For patients receiving haemodialysis dose recommendations for Valcyte 450 mg film-coated tablets cannot be given. This is because an individual dose of Valcyte required for these patients is less than the 450 mg tablet strength. Thus, Valcyte film-coated tablets should not be used in these patients.

Stable liver transplant patients

The pharmacokinetics of ganciclovir from valganciclovir in stable liver transplant patients were investigated in one open label 4-part crossover study (N=28). The bioavailability of ganciclovir from valganciclovir, following a single dose of 900 mg valganciclovir under fed conditions, was approximately 60%. Ganciclovir AUC_0-24h was comparable to that achieved by 5 mg/kg intravenous ganciclovir in liver transplant patients.

Patients with hepatic impairment

The safety and efficacy of Valcyte film-coated tablets have not been studied in patients with hepatic impairment. Hepatic impairment should not affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made.

Patients with cystic fibrosis

In a phase I pharmacokinetic study in lung transplant recipients with or without cystic fibrosis (CF), 31 patients (16 CF/15 non-CF) received post-transplant prophylaxis with 900 mg/day Valcyte. The study indicated that cystic fibrosis had no statistically significant influence on the overall average systemic exposure to ganciclovir in lung transplant recipients. Ganciclovir exposure in lung transplant recipients was comparable to that shown to be efficacious in the prevention of CMV disease in other solid organ transplant recipients.

Valganciclovir is a pro-drug of ganciclovir and therefore effects observed with ganciclovir apply equally to valganciclovir. Ganciclovir was mutagenic in mouse lymphoma cells and clastogenic in mammalian cells. Such results are consistent with the positive mouse carcinogenicity study with ganciclovir. Ganciclovir is a potential carcinogen.

Ganciclovir causes impaired fertility and teratogenicity in animals. Based upon animal studies where aspermatogenesis was induced at ganciclovir systemic exposures below therapeutic levels, it is considered likely that ganciclovir causes inhibition of human spermatogenesis.

Animal data indicate that ganciclovir is excreted in the milk of lactating rats.

Nyctos is a pro-drug of ganciclovir and therefore effects observed with ganciclovir apply equally to Nyctos. Toxicity of Nyctos in pre-clinical safety studies was the same as that seen with ganciclovir and was induced at ganciclovir exposure levels comparable to, or lower than, those in humans given the induction dose.

These findings were gonadotoxicity (testicular cell loss) and nephrotoxicity (uraemia, cell degeneration), which were irreversible; myelotoxicity (anaemia, neutropenia, lymphocytopenia) and gastrointestinal toxicity (mucosal cell necrosis), which were reversible.

Further studies have shown ganciclovir to be mutagenic, carcinogenic, teratogenic, embryotoxic, aspermatogenic (i.e. impairs male fertility) and to suppress female fertility.

Valganciclovir is a pro-drug of ganciclovir and therefore effects observed with ganciclovir apply equally to valganciclovir..

Ganciclovir was mutagenic in mouse lymphoma cells and clastogenic in mammalian cells. Such results are consistent with the positive mouse carcinogenicity study with ganciclovir. Ganciclovir is a potential carcinogen.

Ganciclovir causes impaired fertility and teratogenicity in animals. Based upon animal studies where aspermatogenesis was induced at ganciclovir systemic exposures below therapeutic levels, it is considered likely that ganciclovir causes inhibition of human spermatogenesis.

Animal data indicate that ganciclovir is excreted in the milk of lactating rats.