Elements for a Public Summary. Overview of disease epidemiology. Epidemiology of the disease

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Adele Watkins
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1 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Epidemiology of the disease Cytomegalovirus is found throughout all geographic locations and socioeconomic groups, and infects between 50% and 80% of adults in the United States (>90% worldwide). 1 This infection during pregnancy results in transmission to a developing baby. Between 0.2% and 2% of newborns are infected in studies conducted worldwide. Around 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV. 2 Infection of eyes with cytomegalovirus (Cytomegalovirus retinitis): Reported prevalence of Infection of eyes with cytomegalovirus in people living with HIV in resource-limited settings is variable, ranging from less than 5 percent in southern Africa to over 30 percent in Southeast Asia. Page 38 of 85

2 In Western countries, CMV retinitis is now very rare in people living with HIV, though the problem has not disappeared. In the pre-haart (drugs for AIDS) era, about one-third of patients with AIDS developed CMV retinitis; following the introduction of HAART as well as widespread testing allowing early detection and treatment of HIV the incidence of CMV retinitis declined by over 95 percent in the United States. 4 VI.2.2 Summary of treatment benefits is used to treat cytomegalovirus (CMV) retinitis (eye infection that can cause blindness) in people who have acquired immunodeficiency syndrome (AIDS). is also used to prevent cytomegalovirus (CMV) disease in people who have received a heart, kidney, or kidney-pancreas transplant and who have a chance of getting CMV disease. is in a class of medications called antivirals. It works by preventing the spread of CMV disease or slowing the growth of CMV. VI.2.3 Unknowns relating to treatment benefits There is no experience of valganciclovir use in patients with hepatic impairment. There is no experience of valganciclovir use in elderly patients There is no experience of valganciclovir use during breast feeding VI.2.4 Summary of safety concerns Important identified risks What is known Preventability Hematopoietic cytopenias is known to cause As per section 2 of PIL, and associated infections reduction in the number of white patients are advised to talk and hemorrhage blood cells in the blood to their doctor or (neutropenia) which will make pharmacist before taking patients more likely to get Cipla, if infections, a reduction in the they have low numbers of pigment in the blood that carries white blood cells, red oxygen (anaemia) - which can blood cells or platelets cause tiredness and breathlessness (small cells involved in Page 39 of 85

3 What is known Preventability when they do exercise. blood clotting) in blood. Their doctor will carry out blood tests before they start taking Cipla and more tests will be done while they are taking the tablets. Hypersensitivity Due to the similarity of the As per section 2 of PIL, chemical structure of patients are advised to not valganciclovir (the active take Cipla substance of valganciclovir) and if they are allergic to that of aciclovir and valaciclovir, a valganciclovir or any of the cross-hypersensitivity reaction other ingredients of this between these drugs is possible. medicine or if they are Therefore, valganciclovir is allergic to ganciclovir, contra-indicated in patients with acyclovir or valaciclovir, hypersensitivity to aciclovir and which are medicines used valaciclovir. to treat other virus infections. Fits (Seizures) associated Taking this with As per section 2 of PIL, with co-administration Cipla can cause convulsions (fits) patients are advised to tell with Imipenem-cilastatin their doctor if they are already taking medicines that contain imipenemcilastatin (an antibiotic) Important potential risks Male infertility What is known (Including reason why it is considered a potential risk) In the body the active ingredient in the tablets, valganciclovir, is changed into ganciclovir and therefore effects observed with ganciclovir apply equally to valganciclovir. Toxicity of Page 40 of 85

4 Adverse Pregnancy Outcomes Carcinogenicity Potential for overdose in patients with kidney problems (renal impairment) Potential interactions with other drugs that cause myelosuppression What is known (Including reason why it is considered a potential risk) valganciclovir in pre-clinical safety studies was the same as that seen with ganciclovir. These findings have shown male infertility. As per section 2 of PIL, infertility in men is unknown to occur with valganciclovir as uncommon adverse event which may affect up to 1 in 100 people There are no data from the use of valganciclovir in pregnant women. Its active metabolite, ganciclovir, readily diffuses across the human placenta which can cause pregnancy complications. As per section 2 of PIL, if patients are pregnant or breast-feeding, or are planning to have a baby, they are advised to ask doctor or pharmacist for advice before taking this medicine. Taking when pregnant could harm unborn baby. may cause cancer in the long term. Animal studies have shown ganciclovir to be cancer causing drug. As per section 3 of PIL, the tablets should not be broken or crushed. Patients are advised to 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. It is expected that an overdose of valganciclovir could also possibly result in kidney damage. Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during post-marketing experience. As per section 2 of PIL, strict adherence to dosage recommendations is essential to avoid overdose. Interaction with drugs like zidovudine, didanosine, lamivudine, tenofovir, abacavir, emtricitabine or similar kinds of drugs used to treat AIDS and trimethoprim, trimethoprim/sulpha combinations may reduce production of cells in body which Page 41 of 85

5 Potential interaction with drugs which are excreted through the kidneys What is known (Including reason why it is considered a potential risk) provides immunity. As per section 2 of PIL, patients are advised to consult their doctor before taking these drugs. Since ganciclovir is excreted through the kidney, coadministration of valganciclovir with antiviral drugs that are also excreted by kidney may change the concentrations of valganciclovir and/or the co-administered drug in the blood. Some examples include nucleos(t)ide analog reversetranscriptase inhibitors (NRTIs) (including those used for HBV therapy), e.g. lamivudine, emtricitabine, tenofovir, adefovir and entecavir. As per section 2 of PIL, concomitant use of valganciclovir with any of these drugs should be considered only if the potential benefits outweigh the potential risks Missing information Safety in patients with severe uncontrolled diarrhea or with evidence of malabsorption Pediatric patients < 4 months What is known As per section 4 of PIL, is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. There is no safety data available in patients with severe uncontrolled diarrhoea or with evidence of malabsorption. The safety and efficacy of valganciclovir in the treatment of CMV retinitis have not been established in adequate and wellcontrolled clinical studies in paediatric patients. VI.2.5 Summary of risk minimisation measures by safety concern Not applicable. VI.2.6 Planned post authorisation development plan Not applicable. Page 42 of 85

6 VI.2.7 Summary of changes to the Management Plan over time Major changes to the Management Plan over time Version Date Safety Concerns Comment Version 1 28-Oct-2015 Important identified risk Changes done changed to following: Hematopoietic cytopenias and associated infections and hemorrhage Hypersensitivity Seizures associated with co-administration with Imipenem-cilastatin Important potential risk changed to following : Male infertility Adverse Pregnancy Outcomes Carcinogenicity Potential for overdose in patients with renal impairment Potential interactions with other drugs that cause myelosuppression Potential interaction with drugs which are excreted through the kidneys Missing information changed to following : Safety in patients with Page 43 of 85

7 Version Date Safety Concerns Comment severe uncontrolled diarrhea or with evidence of malabsorption Pediatric patients < 4 months Page 44 of 85

PATIENT INFORMATION LEAFLET

PATIENT INFORMATION LEAFLET Page 1 of 6 PATIENT INFORMATION LEAFLET: INFORMATION FOR THE USER Ganciclovir 500 mg Powder for Infusion * Read all of this leaflet carefully before you start taking this medicine