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Drug Details

VALCYTE Film-coated Tablets

• Drug Class Description
  Anti-infectives, Antivirals for Systemic use and direct Acting Antivirals
• Generic Name
  Valganciclovir
• Presentation
  Film-coated tablets Pink, convex oval film-coated tablets, with “VGC” embossed on one side and “450” on the other side.
• Description
  Each tablet contains 496.3 mg of valganciclovir hydrochloride equivalent to 450 mg of valganciclovir (as free base).
• Indications
  Valcyte is indicated for the induction and maintenance treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Valcyte is indicated for the prevention of CMV disease in CMV-negative patients who have received a solid organ transplant from a CMV-positive donor.
• Adult Dosage
  

  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.

  Standard dosage in adults

  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.

  Caution – Strict adherence to dosage recommendations is essential to avoid overdose

  Prevention of CMV disease in solid organ transplantation:

  For patients who have received a transplant, the recommended dose is 900 mg once daily, starting within 10 days of transplantation and continuing until 100 days post transplantation.

  Special dosage instructions

  Patients with 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.

  CrCl (ml/min)	Induction dose of valganciclovir	Maintenance/Prevention dose of valganciclovir
  60	900 mg twice daily	900 mg once daily
  40 – 59	450 mg twice daily	450 mg once daily
  25 – 39	450 mg once daily	225 mg once daily
  10 – 24	225 mg once daily	125 mg once daily
  <10	200 mg three times a week after dialysis	100 mg three times a week after dialysis

  Patients undergoing haemodialysis:

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

   

  Patients with hepatic impairment

  Safety and efficacy of VALCYTE have not been studied in patients with hepatic impairment.

   

  Children and adolescents (less than 18 years of age):

  Valcyte is not recommended for use in children below 18 years of age due to lack of data on safety and efficacy in this patient population.

   

  Elderly patients:

  Safety and efficacy of VALCYTE have 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 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.

  VALCYTE powder for oral solution requires reconstitution prior to oral administration. Two oral dosing dispensers with graduations in 25 mg up to 500 mg are provided. It is recommended that patients use the dispenser.

• Child Dosage
  Paediatric patients: Safety and efficacy have not been established in this patient population (See Special Precautions).
• Elderly Dosage
  Safety and efficacy have not been established in this patient population.
• Contra Indications
  

  Valcyte is contra-indicated in patients with hypersensitivity to valganciclovir, ganciclovir or to any of the excipients.

  Due to the similarity of the chemical structure of Valcyte and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these drugs is possible. Therefore, Valcyte is contra-indicated in patients with hypersensitivity to aciclovir and valaciclovir.

• Special Precautions
  

  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.

  Standard dosage in adults

  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.

  Elderley patients:
  
  Safety and efficacy have not been established in this patient population.

  Prevention of CMV disease in solid organ transplantation:

  For patients who have received a transplant, the recommended dose is 900 mg (two Valcyte 450 mg tablets) once daily, starting within 10 days of transplantation and continuing until 100 days posttransplantation. Whenever possible, the tablets should be taken with food.

  Special dosage instructions

  Patients with 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 males= (140 - age [years] x body weight [kg]
                      (72) x (0.011 x serum creatinine [micromol/L])

  For females = 0.85 × male value

  CrCl (mL/min)	Induction dose of valganciclovir	Maintenance/Prevention dose of valganciclovir
  ≥ 60	900 mg (2 tablets) twice daily	900 mg (2 tablets) once daily
  40-59	450 mg (1 tablet) twice daily	450 mg (1 tablet) once daily
  25-39	450 mg (1 tablet) once daily	450 mg (1 tablet) every 2 days
  10-24	450 mg (1 tablet) every 2 days	450 mg (1 tablet) twice weekly

  Patients undergoing haemodialysis:

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

  Patients with hepatic impairment:

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

  Paediatric patients:

  Valcyte is not recommended for use in the paediatric population due to insufficient data on safety and efficacy

  Patients with severe leucopenia, 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.

  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 (see section 4.4 ). Avoid direct contact of broken or crushed tablets with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with sterile water, or plain water if sterile water is unavailable.

• Interactions
  

  Drug interactions with valganciclovir

  In-vivo drug interaction studies with Valcyte have not been performed. Since valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions associated with ganciclovir will be expected for valganciclovir.

  Effects of other medicinal products on ganciclovir

  Imipenem-cilastatin

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

  Probenecid

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

  Effects of ganciclovir on other medicinal products

  Zidovudine

  When zidovudine was given in the presence of oral ganciclovir there was a small (17 %), but statistically significant increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine, although this was not statistically significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, some patients may not tolerate concomitant therapy at full dosage.

  Didanosine

  Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both intravenous and oral). At ganciclovir oral doses of 3 and 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise at intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67 % has been observed. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity.

  Mycophenolate Mofetil

  Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment to whom MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed and the patients monitored carefully. Since both MMF and ganciclovir have the potential to cause neutropenia and leucopenia, patients should be monitored for additive toxicity.

  Zalcitabine

  No clinically significant pharmacokinetic changes were observed after concomitant administration of ganciclovir and zalcitabine. Both valganciclovir and zalcitabine have the potential to cause peripheral neuropathy and patients should be monitored for such events.

  Stavudine

  No clinically significant interactions were observed when stavudine and oral ganciclovir were given in combination.

  Trimethoprim

  No clinically significant pharmacokinetic interaction was observed when trimethoprim and oral ganciclovir were given in combination. However, there is a potential for toxicity to be enhanced since both drugs are known to be myelosuppressive and therefore both drugs should be used concomitantly only if the potential benefits outweigh the risks.

  Other antiretrovirals

  At clinically relevant concentrations, there is unlikely to be either a synergistic or antagonistic effect on the inhibition of either HIV in the presence of ganciclovir or CMV in the presence of a variety of antiretroviral drugs. Metabolic interactions with, for example, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely due to the lack of P450 involvement in the metabolism of either valganciclovir or ganciclovir.

  Other potential drug interactions

  Toxicity may be enhanced when valganciclovir is co-administered with, or is given immediately before or after, other drugs that inhibit replication of rapidly dividing cell populations such as occur in the bone marrow, testes and germinal layers of the skin and gastrointestinal mucosa. Examples of these types of drugs are dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations, nucleoside analogues and hydroxyurea.

  Since ganciclovir is excreted through the kidney, toxicity may also be enhanced during co-administration of valganciclovir with drugs that might reduce the renal clearance of ganciclovir and hence increase its exposure. The renal clearance of ganciclovir might be inhibited by two mechanisms: (a) nephrotoxicity, caused by drugs such as cidofovir and foscarnet, and (b) competitive inhibition of active tubular secretion in the kidney by, for example, other nucleoside analogues.

  Therefore, all of these drugs should be considered for concomitant use with valganciclovir only if the potential benefits outweigh the potential risks.

• Adverse Drug Reactions
  

  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 usage can be expected to occur with valganciclovir. All of the undesirable effects observed in valganciclovir clinical studies have been previously observed with ganciclovir. The most commonly reported adverse drug reactions following administration of valganciclovir are neutropenia, anaemia and diarrhoea.

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

  Severe neutropenia (< 500 ANC/μL) is seen more frequently in CMV retinitis patients undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir or oral ganciclovir.

  The frequency of adverse reactions reported in clinical trials with either valganciclovir, oral ganciclovir, or intravenous ganciclovir is presented in the table below. Frequencies are defined as very common (1/10), common (1/100 <1/10), uncommon (1/1000 < 1/100), rare (1/10,000 <1/1000) and very rare (<1/10,000). 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. No reactions with rare or very rare frequencies have been identified from clinical experience. 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.

  Body System	Very Common 1/10)	Common 1/100 <1/10)	Uncommon1/1000 < 1/100)
  Infections and infestations		Oral candidiasis, sepsis (bacteraemia, viraemia), cellulitis, urinary tract infection
  Blood and lymphatic system disorders	(severe) neutropenia, anaemia	Severe anaemia, (severe) thrombocytopenia, (severe) leucopenia, (severe) pancytopenia	Bone marrow depression
  Immune system disorders			Anaphylactic reaction
  Metabolic and nutrition disorders		Appetite decreased, anorexia
  Psychiatric disorders		Depression, anxiety, confusion, abnormal thinking	Agitation, psychotic disorder
  Nervous system disorders		Headache, insomnia, dysgeusia, (taste disturbance), hypoaesthesia, paraesthesia, peripheral neuropathy, dizziness (excluding vertigo), convulsions	tremor
  Eye disorders		Macular oedema, retinal detachment, vitreous floaters, eye pain	Vision abnormal, conjunctivitis
  Ear and labyrinth disorders		Ear pain	Deafness
  Cardiac disorders			Arrhythmias
  Vascular disorders			Hypotension
  Respiratory, thoracic and mediastinal disorders	Dyspnoea	Cough
  Gastrointestinal disorders	Diarrhoea	Nausea, vomiting, abdominal pain, abdominal pain upper, dyspepsia, constipation, flatulence, dysphagia	Abdominal distension, mouth ulcerations, pancreatitis
  Hepato-biliary disorders		(severe) hepatic function abnormal, blood alkaline phosphatase increased, aspartate aminotransferase increased	Alanine aminotransferase increased
  Skin and subcutaneous disorders		Dermatitis, night sweats, pruritis	Alopecia, urticaria, dry skin
  Musculoskeletal, connective tissue and bone disorders		Back pain, myalgia, arthralgia, muscle cramps
  Renal and urinary disorder		Creatinine clearance renal decreased, renal impairment	Haematuria, renal failure
  Reproductive system and breast disorders			Male infertility
  General disorders and administration site conditions		Fatigue, pyrexia, rigors, pain, chest pain, malaise, asthenia
  Investigations		Weight decreased, blood creatinine increased