Valganciclovir 450mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Valganciclovir hydrochloride
Available from:
Mawdsley-Brooks & Company Ltd
ATC code:
J05AB14
INN (International Name):
Valganciclovir hydrochloride
Dosage:
450mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05030202

Valganciclovir with food and drink

Valganciclovir should be taken with food. If you are unable to eat for

any reason, you should still take your dose of Valganciclovir as usual.

Pregnancy and breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or

are planning to have a baby, ask your doctor or pharmacist for advice

before taking this medicine.

You should not take Valganciclovir if you are pregnant unless your

doctor recommends it.

Taking Valganciclovir when you are pregnant could harm your unborn

baby.

You must not take Valganciclovir if you are breastfeeding. If your

doctor wants you to begin treatment with Valganciclovir you must stop

breastfeeding before you start to take your tablets.

Women of childbearing age must use effective contraception when

taking Valganciclovir.

Men whose partners could become pregnant should use condoms

while taking Valganciclovir and should continue to use condoms for 90

days after treatment has finished.

Driving and using machines

Do not drive or use any tools or machines if you feel dizzy, tired, shaky

or confused while taking this medicine.

Ask your doctor or pharmacist for advice before taking any medicine.

Always take this medicine exactly as your doctor or pharmacist has

told you. Check with your doctor or pharmacist if you are not sure.

You have to be careful when handling your tablets. Do not break or

crush them. You should swallow them whole and with food whenever

possible. If you accidentally touch damaged tablets, wash your hands

thoroughly with soap and water. If any powder from the tablets gets in

your eyes, rinse your eyes with sterile water or clean water if you do

not have sterile water.

You must stick to the number of tablets as instructed by your

doctor to avoid overdose.

Valganciclovir tablets should, whenever possible, be taken with food –

see section 2.

Other suitable dosage forms are available for children and

adolescents who need dose adjustments.

Adults:

Prevention of CMV disease in transplant patients

You should start to take this medicine within 10 days of your transplant.

The recommended dose is two tablets taken ONCE daily.

You should continue with this dose for up to 100 days following your

transplant. If you have received a kidney transplant, your doctor may

advise you to take the tablets for 200 days.

Treatment of active CMV retinitis in AIDS patients (called

induction treatment)

The recommended dose Valganciclovir is two tablets taken TWICE a

day for 21 days (three weeks).

Do not take this dose for more than 21 days unless your doctor tells

you to, as this may increase your risk of possible side effects.

Longer term treatment to prevent recurrence of active

inflammation in AIDS patients with CMV retinitis (called

maintenance treatment)

The recommended dose is two tablets taken ONCE daily. You should

try to take the tablets at the same time each day.

Your doctor will advise you how long you should continue to take

Valganciclovir. If your retinitis worsens while you are on this dose, your

doctor may tell you to repeat the induction treatment (as above) or

may decide to give you a different medicine to treat the CMV infection.

Valganciclovir belongs to a group of medicines, which work directly

to prevent the growth of viruses. In the body the active ingredient in

the tablets, valganciclovir, is changed into ganciclovir. Ganciclovir

prevents a virus called cytomegalovirus (CMV) from multiplying and

invading healthy cells. In patients with a weakened immune system,

CMV can cause an infection in the body’s organs. This can be life

threatening.

Valganciclovir is used:

for treatment of CMV-infections of the retina of the eye in patients

with acquired immunodeficiency syndrome (AIDS). CMV-infection of

the retina of the eye can cause vision problems and even blindness.

to prevent CMV-infections in patients who are not infected with CMV

and who have received an organ transplant from somebody who

was infected by CMV.

Do not take Valganciclovir

if you are allergic to valganciclovir or any of the other ingredients of

this medicine (listed in section 6).

if you are allergic to ganciclovir, acyclovir or valaciclovir, which are

medicines used to treat other virus infections.

if you are breastfeeding.

Warnings and precautions

Talk to your doctor or pharmacist before taking Valganciclovir.

if you have low numbers of white blood cells, red blood cells or

platelets (small cells involved in blood clotting) in your blood. Your

doctor will carry out blood tests before you start taking Valganciclovir

tablets and more tests will be done while you are taking the tablets.

if you are having radiotherapy or haemodialysis

if you have a problem with your kidneys. Your doctor may need to

prescribe a reduced dose for you and may need to check your

blood frequently during treatment.

if you are currently taking ganciclovir capsules and your doctor

wants you to switch to Valganciclovir tablets. It is important that you

do not take more than the number of tablets prescribed by your

doctor or you could risk an overdose.

Other medicines and Valganciclovir

Tell your doctor or pharmacist if you are taking, have recently taken or

might take any other medicines, including medicines obtained without

a prescription.

If you take other medicines at the same time as taking Valganciclovir

the combination could affect the amount of drug that gets into your

blood stream or could cause harmful effects.

Tell your doctor if you are already taking medicines that contain any of

the following:

imipenem-cilastatin (an antibiotic). Taking this with Valganciclovir

can cause convulsions (fits)

zidovudine, didanosine, lamivudine, tenofovir, abacavir,

emtricitabine or similar kinds of drugs used to treat AIDS

ribavirin, pegylated interferons, adefovir and entecavir used to treat

Hepatitis B/C

probenecid (a medicine against gout). Taking probenecid and

Valganciclovir at the same time could increase the amount of

ganciclovir in your blood

mycophenolate mofetil (used after transplantations)

vincristine, vinblastine, adriamycin, hydoxyurea or similar kinds of

drugs to treat cancer

cidofovir or foscarnet used against viral infections

trimethoprim, trimethoprim/sulpha combinations and dapsone

(antibiotics)

pentamidine (drug to treat parasite or lung infections)

flucytosine or amphotericin B (anti-fungal agents)

PACKAGE LEAFLET:INFORMATION FOR THE PATIENT

SZ00000LT000

Valganciclovir 450 mg film-coated tablets

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same

as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Continued on the next page >>

Valganciclovir

What is in this leaflet:

What Valganciclovir is and what it is used for

What you need to know before you take Valganciclovir

How to take Valganciclovir

Possible side effects

How to store Valganciclovir

Content of the pack and other information

What you need to know before you take

Valganciclovir

What Valganciclovir is and what it is used for

How to take Valganciclovir

SZ00000LT000

Elderly patients

Valganciclovir has not been studied in elderly patients.

Patients with kidney problems

If your kidneys are not working properly, your doctor may instruct you

to take fewer tablets each day or only to take your tablets on certain

days each week. It is very important that you only take the number of

tablets prescribed by your doctor.

Patients with liver problems

Valganciclovir has not been studied in patients with liver problems.

Use in children and adolescents:

Prevention of CMV disease in transplant patients

Children should start to take this medicine within 10 days of their

transplant. The dose given will vary depending on the size of the

child and should be taken ONCE daily. Your doctor will decide the

most appropriate dose based on your child’s height, weight and renal

function. You should continue with this dose for up to 100 days. If your

child has received a kidney transplant, your doctor may advise you to

take the dose for 200 days.

If you take more Valganciclovir than you should

Contact your doctor or hospital immediately if you have taken, or think

that you have taken, more tablets than you should. Taking too many

tablets can cause serious side effects, particularly affecting your blood

or kidneys. You may need hospital treatment.

If you forget to take Valganciclovir

If you forget to take your tablets take the missed dose as soon as you

remember and take the next dose at the usual time. Do not take a

double dose to make up for the forgotten tablets.

If you stop taking Valganciclovir

You must not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your

doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not

everybody gets them.

Allergic reactions

Up to 1 in every 100 people may have a sudden and severe allergic

reaction to valganciclovir (anaphylactic shock). STOP taking

Valganciclovir and go to the accident and emergency department at

your nearest hospital if you experience any of the following:

a raised, itchy skin rash (hives)

sudden swelling of the throat, face, lips and mouth which may

cause difficulty swallowing or breathing

sudden swelling of the hands, feet or ankles.

The side effects that have occurred during treatment with

valganciclovir or ganciclovir are given below:

Very common (may affect more than 1 in 10 people):

Effects on the blood: a reduction in the number of white blood cells

in the blood (neutropenia) - which will make you more likely to get

infections, a reduction in the pigment in the blood that carries

oxygen (anaemia) - which can cause tiredness and breathlessness

when you exercise

Effects on breathing: feeling short of breath or having trouble

breathing (dyspnoea)

Effects on the stomach and digestive system: diarrhea

Common (may affect up to 1 in 10 people):

Effects on the blood: a reduction in the number of leucocytes (blood

cells that fight infection) in the blood (leucopenia), a reduction in the

number of platelets in the blood (thrombocytopenia) - which can

cause bruising and bleeding, a reduction in the number of several

types of blood cells at the same time (pancytopenia)

Effects on the nervous system: headache, difficulty sleeping

(insomnia), strange tastes (dysgeusia), becoming less sensitive to

touch (hypoaesthesia), prickly or tingling skin (paraesthesia), loss

of feeling in the hands or feet (peripheral neurophathy), dizziness,

fits (convulsions)

Effects in the eye: eye pain, swelling within the eye (oedema),

separation of the inner lining of the eye (detached retina), seeing

floaters

Effects in the ear: earache

Effects on breathing: coughing

Effects on the stomach and digestion: feeling and being sick,

stomachache, constipation, wind, indigestion (dyspepsia), difficulty

swallowing (dysphagia)

Effects on the skin: inflamed skin (dermatitis), itching (pruritis),

sweating at night

Effects on the muscles, joints or bones: back pain, pain in the muscles

(myalgia) or joints (arthralgia), stiff muscles (rigor), muscle cramps

Infections: fungal infection in the mouth (oral candidiasis), infections

caused by bacteria or viruses in the blood, inflammation of cellular

tissue (cellulitis), inflammation or infection of the kidneys or bladder

Effects in the liver: a rise in some liver enzymes, which will only be

seen during blood tests

Effects in the kidney: changes to the normal working of the kidneys

Effects on eating: loss of appetite (anorexia), weight loss

General effects: tiredness, fever, pain, chest pain, loss of energy

(asthenia), generally feeling unwell (malaise)

Effects on mood or behaviour: depression, feeling anxious,

confused, having unusual thoughts

Uncommon (may affect up to 1 in 100 people):

Effects in the heart: changes to the normal heart beat (arrhythmia)

Effects on circulation: low blood pressure (hypotension), which can

cause you to feel light headed or faint

Effects on the blood: a decrease in the production of blood cells in

the bone marrow

Effects in the nerves: shaking or trembling

(tremor)

Effects in the eyes: red, swollen eyes (conjunctivitis), abnormal

vision

Effects in the ears: deafness

Effects on the stomach or digestion: swollen stomach, mouth ulcers,

inflammation of the pancreas

(pancreatitis) where you may notice severe pain in the stomach and

back

Effects on the skin: hair loss (alopecia), itchy rash or swellings

(urticaria), dry skin

Effects in the kidneys: blood in the urine (haematuria), kidney failure

Effects in the liver: a rise in the liver enzyme called alanine

aminotransferase (which will only be seen during blood tests)

Effects on fertility: infertility in men

Effects on mood or behaviour: having unusual changes in mood

and behaviour, losing contact with reality such as hearing voices or

seeing things that are not there, feeling agitated

Rare (may affect up to 1 in 1000 people):

Effects on the blood: failure of the production of all types of blood

cells (red blood cells, white blood cells and platelets) in the bone

marrow

Separation of the inner lining of the eye (detached retina) has only

happened in AIDS patients treated with valganciclovir for CMV infection.

Additional side effects in children and adolescents

The side effects reported in children and adolescents are similar to the

side effects reported for adults.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This

includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme:

www.mhra.gov.uk/yellowcard. By reporting side effects you can help

provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Shelf life for bottles:

After first opening: 2 months

Do not use this medicine after the expiry date which is stated on the

label, carton, or bottle after EXP. The expiry date refers to the last day

of that month.

This medicine does not require any special storage condition.

Do not throw away medicines via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use.

These measures will help protect the environment.

What Valganciclovir contains

The active substance is valganciclovir.

Each tablet contains 496.3 mg of valganciclovir hydrochloride

equivalent to 450 mg of valganciclovir (as free base).

The other ingredients are:

Tablet core: Cellulose microcrystalline (PH101), Crospovidone

(Type A), Povidone (K-30), Stearic acid 50

Film-coating: Opadry Pink 15B24005:

Hypromellose (3 cP), Hypromellose (6 cP), Titanium dioxide (E171),

Macrogol 400 , Iron oxide red (E172), Polysorbate 80

What Valganciclovir looks like and contents of the pack

Valganciclovir are pink, oval, biconvex, film coated tablets (16.7 x

7.8 mm), debossed with “J” on one side and “156” on the other side

embossed on the other side.

Aluminium/PVC/Aluminium/OPA blister: 10, 30, 60, 90, 120

film-coated tablets.

HDPE container with child resistant polypropylene screw caps: 60

film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Sandoz Limited, Frimley Business Park, Frimley, Camberley,

Surrey, GU16 7SR, United Kingdom

Manufacturer

Salutas Pharma GmbH, Otto- von- Guericke- Allee 1, 39179 Barleben,

Germany or Lek Pharmaceuticals d.d., Verovskova ulica 57, 1526

Ljubljana, Slovenia or LEK S.A., Ul. Domaniewska 50 C, 02- 672

Warszawa, Poland

This leaflet was last revised in 11/2014.

Possible side effects

How to store Valganciclovir

Content of the pack and other information

1.

NAME OF THE MEDICINAL PRODUCT

Valganciclovir 450 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 496.3 mg of valganciclovir hydrochloride equivalent to

450 mg of valganciclovir (as free base).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Oval, biconvex, pink colored film-coated tablets approx16.83 x 7.95 mm.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Valganciclovir is indicated for the induction and maintenance treatment of cytomegalovirus

(CMV) retinitis in adult patients with acquired immunodeficiency syndrome (AIDS).

Valganciclovir is indicated for the prevention of CMV disease in CMV-negative adults and

children (aged from birth to 18 years) who have received a solid organ transplant from a

CMV-positive donor.

4.2

Posology and method of administration

Posology

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

(see sections 4.4 and 4.9).

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

Valganciclovir 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 (see

section 4.4).

Maintenance treatment of CMV retinitis:

Following induction treatment, or in patients with inactive CMV retinitis, the recommended

dose is 900 mg valganciclovir (two Valganciclovir 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 valganciclovir 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 Valganciclovir 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 (see

sections 4.4, 4.8 and 5.1).

For patients who have received a solid organ transplant other than kidney, the recommended

dose is 900 mg (two Valganciclovir 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 valganciclovir 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, valganciclovir 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 ages. Since renal clearance decreases with age,

valganciclovir should be administered to elderly patients with special consideration of their

renal status (see table below). (See section 5.2)

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

(see sections 4.4 and 5.2).

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

following formulae:

For males =

For females =

0.85 × male value

Creatinine clearance

) (ml/min)

Induction dose of

valganciclovir

Maintenance/Prevention dose

of valganciclovir

40 – 59

25 – 39

10 – 24

< 10

900 mg (2 tablets) twice daily

450 mg (1 tablet) twice daily

450 mg (1 tablet) once daily

450 mg (1 tablet) every 2 days

not recommended

900 mg (2 tablets) once daily

450 mg (1 tablet) once daily

450 mg (1 tablet) every 2 days

450 mg (1 tablet) twice weekly

not recommended

Patients undergoing haemodialysis:

For patients on haemodialysis (Clcr < 10 ml/min) a dose recommendation cannot be given.

Thus Valganciclovir film-coated tablets should not be used in these patients (see sections 4.4

and 5.2).

Patients with hepatic impairment:

Safety and efficacy of valganciclovir tablets have not been established in patients with hepatic

impairment (see section 5.2).

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

See section 4.4 before initiation of therapy. If there is a significant deterioration of blood cell

counts during therapy with valganciclovir, treatment with haematopoietic growth factors

and/or dose interruption should be considered (see section 4.4).

Method of administration

Valganciclovir is administered orally, and whenever possible, should be taken with food (see

section 5.2).

Valganciclovir is also available as an oral suspension for use in patients who are unable to

swallow tablets (please refer to the Summary of Product Characteristics for oral suspension

containing valganciclovir).

Precautions to be taken before handling or administering the medicinal product

The tablets should not be broken or crushed. Since valganciclovir is considered a potential

teratogen and carcinogen in humans, caution should be observed in handling broken

tablets (see section 4.4). Avoid direct contact of broken or crushed tablets with skin or

mucous membranes. If such contact occurs, wash thoroughly with soap and water,

rinse eyes thoroughly with sterile water, or plain water if sterile water is unavailable.

4.3

Contraindications

Valganciclovir is contra-indicated in patients with hypersensitivity to valganciclovir,

ganciclovir or to any of the excipients listed in section 6.1.

Valganciclovir is contra-indicated during breast-feeding (see section 4.6).

4.4

Special warnings and precautions for use

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 valganciclovir 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. Valganciclovir should,

therefore, be considered a potential teratogen and carcinogen in humans with the potential to

cause birth defects and cancers (see section 5.3). It is also considered likely that

valganciclovir 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 (see sections 4.6, 4.8 and 5.3).

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

term.

Myelosupression

Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow

failure and aplastic anaemia have been observed in patients treated with valganciclovir (and

ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500

cells/

l, or the platelet count is less than 25000/

l, or the haemoglobin level is less than 8g/dl

(see sections 4.2 and 4.8).

When extending prophylaxis beyond 100 days the possible risk of developing leukopenia and

neutropenia should be taken into account (see sections 4.2, 4.8 and 5.1).

Valganciclovir 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 (see section 4.2).

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 valganciclovir 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 valganciclovir tablets (see sections 4.2 and 4.9).

Renal impairment

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

required (see sections 4.2 and 5.2).

Valganciclovir film-coated tablets should not be used in patients on haemodialysis (see

sections 4.2 and 5.2).

Use with other medicines

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir.

Valganciclovir should not be used concomitantly with imipenem-cilastatin unless the

potential benefits outweigh the potential risks (see section 4.5).

Patients treated with valganciclovir 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 (see section 4.5).

The controlled clinical study using valganciclovir for the prophylactic treatment of CMV

disease in transplantation, as detailed in section 5.1, did not include lung and intestinal

transplant patients. Therefore, experience in these transplant patients is limited.

4.5

Interaction with other medicinal products and other forms of interaction

Drug interactions with valganciclovir

In-vivo drug interaction studies with valganciclovir have not been performed. Since

valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions

associated with ganciclovir will be expected for valganciclovir.

Drug interactions with ganciclovir

Pharmacokinetic interactions

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 valganciclovir should be

closely monitored for ganciclovir toxicity.

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with IV

ganciclovir. At intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of

didanosine ranging from 38 to 67% has been observed confirming a pharmacokinetic

interaction during the concomitant administration of these drugs. There was no significant

effect on ganciclovir concentrations. Patients should be closely monitored for didanosine

toxicity e.g. pancreatitis (see section 4.4).

Other

antiretrovirals

Cytochrome P450 isoenzymes play no role in ganciclovir pharmacokinetics. As a

consequence,

pharmacokinetic

interactions with protease inhibitors and non-nucleoside

reverse transcriptase inhibitors are not

anticipated.

Pharmacodynamic interactions

Imipenem-cilastatin

Convulsions have been reported in patients taking ganciclovir and imipenem- cilastatin

concomitantly and a pharmacodynamic interaction between these two drugs cannot be

discounted

. These drugs should not be used concomitantly unless the potential benefits

outweigh the potential risks (see section 4.4).

Zidovudine

Both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia. A

pharmacodynamic

interaction may occur during concomitant administration of these drugs.

Some patients may not tolerate

concomitant

therapy at full dosage (see section

4.4).

Potential drug interactions

Toxicity may be enhanced when ganciclovir/valganciclovir is co-administered with other

drugs known to be myelosuppressive or associated with renal impairment. This includes

nucleoside (e.g. zidovudine, didanosine, stavudine) and nucleotide analogues (e.g. tenofovir,

adefovir), immunosuppressants (e.g. ciclosporin, tacrolimus, mycophenolate, mofetil),

antineoplastic agents (e.g. doxorubicin, vinblastine, vincristine, hydroxyurea) and anti-

infective agents (trimethoprim/sulphonamides, dapsone, amphotericin B, flucytosine,

pentamidine). Therefore, these drugs should only be considered for concomitant use with

valganciclovir if the potential benefits outweigh the potential risks (see section 4.4).

4.6

Fertility, pregnancy and lactation

Contraception in males and females

As a result of the potential for reproductive toxicity and teratogenicity women of child-

bearing potential must be advised to use effective contraception during and for at least 30

days after treatment. Male patients must be advised to practice barrier contraception during,

and for at least 90 days following treatment with valganciclovir unless it is certain that the

female partner is not at risk of pregnancy (see sections 4.4 and 5.3).

Pregnancy

The safety of valganciclovir for use in pregnant women has not been established. Its active

metabolite, ganciclovir, readily diffuses across the human placenta. Based on its

pharmacological mechanism of action and reproductive toxicity observed in animal studies

with ganciclovir (see section 5.3) there is a theoretical risk of teratogenicity in humans.

Valganciclovir should not be used in pregnancy unless the therapeutic benefit for the mother

outweighs the potential risk of teratogenic damage to the foetus.

Breast-feeding

It is unknown if ganciclovir is excreted in human breast milk, but the possibility of

ganciclovir being excreted in the breast milk and causing serious adverse reactions in the

nursing infant cannot be discounted. Animal data

indicate

that ganciclovir is excreted in the

milk of lactating rats. Therefore, breast-feeding must be discontinued during treatment with

valganciclovir (see sections 4.3 and 5.3).

Fertility

No human data on the effect of valganciclovir on fertility are available. Fertility studies have

not been repeated with valganciclovir because of the rapid and extensive conversion of

valganciclovir to ganciclovir in the body. Ganciclovir is associated with impaired fertility in

animal studies (see section 5.3).

4.7

Effects on ability to drive and use machines

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 valganciclovir

and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness, including

the patient’s ability to drive and operate machinery.

4.8

Undesirable effects

a Summary of the safety profile

Valganciclovir is a prodrug of ganciclovir, 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.

In patients treated with valganciclovir/ganciclovir the most serious and frequent adverse drug

reactions are haematological reactions and include neutropenia, anaemia and

thrombocytopenia - see section 4.4.

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

< 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

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/

and skin reactions

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

Body System

Very Common

(

1/10)

Common

(

1/100 to <

1/10)

Uncommon

(

1/1000 to

< 1/100)

Rare

(

1/10,000 to

< 1/1000)

Infections and

infestations

Candida

infections

including oral

candidiasis, u

pper

respiratory tract

infection

Sepsis, influenza,

urinary tract

infection

, cellulitis

Blood and

lymphatic

system disorders

Neutropenia,

anaemia

Thrombocytope

nia, leukopenia,

pancytopenia

Bone marrow

failure

Aplastic anaemia,

agranulocytosis*,

granulocytopenia*

Immune system

disorders

Hypersensitivity

Anaphylactic

reaction*

Metabolism and

nutrition

disorders

Decreased

appetite

Weight decreased

Psychiatric

disorders

Depression, anxiety,

confusional

state

Agitation,

psychotic

disorder,

hallucinations

, abnormal

thinking

Nervous system

disorders

Headache

Insomnia,

dysgeusia (taste

disturbance),

hypoaesthesia,

paraesthesia,

peripheral

neuropathy,

dizziness,

convulsion

Tremor

Eye disorders

Macular oedema,

retinal

detachment**,

vitreous floaters,

eye pain, visual

impairment,

conjunctivitis

Ear and labyrinth

disorders

Ear pain

Deafness

Cardiac

disorders

Arrhythmia

Vascular

disorders

Hypotension

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea, cough

Gastrointestinal

disorders

Diarrhoea, nausea,

vomiting,

abdominal pain

Abdominal pain

upper, dyspepsia,

constipation,

flatulence,

dysphagia, mouth

ulceration,

pancreatitis,

abdominal

distension

Public Assessment Report

Decentralised Procedure

Valganciclovir 450mg film-coated tablets

Procedure No: UK/H/5641/001/DC

UK Licence No: PL 17780/0688

Winthrop Pharmaceuticals UK Limited

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

2

LAY SUMMARY

Valganciclovir 450mg film-coated tablets

(Valganciclovir hydrochloride, 450mg, film-coated tablets)

This is a summary of the Public Assessment Report (PAR) for Valganciclovir 450mg film-coated tablets

(PL 17780/0688; UK/H/5641/001/DC). It explains how Valganciclovir 450mg film-coated tablets were

assessed and their authorisation recommended, as well as their conditions of use. It is not intended to

provide practical advice on how to use Valganciclovir 450mg film-coated tablets.

For practical information about using Valganciclovir 450mg film-coated tablets, patients should read the

package leaflet or contact their doctor or pharmacist.

Valganciclovir 450mg film-coated tablets may be referred to as Valganciclovir tablets in this report.

What are Valganciclovir tablets and what are they used for?

Valganciclovir tablets are a medicine that contains the active ingredient, valganciclovir (as

valganciclovir hydrochloride).

Valganciclovir 450mg film-coated tablets are used:

for the treatment of cytomegalovirus (CMV)-infections of the retina of the eye in patients with

acquired immunodeficiency syndrome (AIDS). CMV-infection of the retina of the eye can cause

vision problems and even blindness;

to prevent CMV-infections in adults and children who are not infected with CMV and who have

received an organ transplant from somebody who was infected by CMV.

Valganciclovir tablets are a ‘generic’ medicine. This means that Valganciclovir tablets are similar to a

reference medicine already authorised in the European Union (EU) called Valcyte 450mg film-coated

tablets (Roche Nederland B.V., the Netherlands).

How do Valganciclovir tablets work?

The active ingredient, valganciclovir, belongs to a group of medicines, which work directly to prevent

the growth of viruses. In the body, valganciclovir is changed into ganciclovir. Ganciclovir prevents a

virus called cytomegalovirus (CMV) from multiplying and invading healthy cells. In patients with a

weakened immune system, CMV can cause an infection in the body’s organs. This can be life

threatening.

How are Valganciclovir tablets used?

Valganciclovir tablets

are taken by mouth. The tablets should be swallowed whole and with food

whenever possible. The tablets should always be taken as instructed by the prescribing doctor. The

patient should check with his/her doctor or pharmacist if unsure.

To avoid overdose, the patient should only take the number of tablets as instructed by the prescribing

doctor.

Care should be taken when handling the tablets. The tablets should not be broken or crushed. If damaged

tablets are accidentally touched, the hands should be thoroughly washed with soap and water. The eyes

should be rinsed with sterile water (or clean water, if sterile water is not available), if any of the powder

from the tablet gets into the eyes.

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

3

Please read section 3 of the package leaflet (PL) for detailed information on dosing recommendations,

the route of administration, and the duration of treatment.

Valganciclovir tablets can only be obtained with a prescription.

How have Valganciclovir tablets been studied?

As Valganciclovir tablets are a generic medicine, studies in patients have been limited to tests to

determine that they are bioequivalent to the reference medicine, Valcyte 450 mg film-coated tablets

(Roche Pharma AG, Germany). Two medicines are bioequivalent when they produce the same levels of

the active substance in the body.

What are the benefits and risks of Valganciclovir tablets?

Because Valganciclovir tablets are a generic medicine and are bioequivalent to the reference medicine,

their benefits and risks are taken as being the same as those of the reference medicine.

Why are Valganciclovir tablets approved?

It was concluded that, in accordance with EU requirements, Valganciclovir tablets have been shown to

have comparable quality and to be bioequivalent to the reference medicine, Valcyte 450mg tablets

(Roche Pharma AG, Germany). Therefore, the view was that, as for Valcyte 450mg film-coated tablets

(Roche Pharma AG, Germany), the benefits of these tablets outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of Valganciclovir tablets?

A Risk Management Plan has been developed to ensure that Valganciclovir tablets are used as safely as

possible. Based on this plan, safety information has been included in the Summary of Product

Characteristics and the package leaflet for Valganciclovir tablets, including the appropriate precautions

to be followed by healthcare professionals and patients.

Other information about Valganciclovir tablets

The Czech Republic, France, Poland, Romania and the UK agreed to grant a Marketing Authorisation

for Valganciclovir tablets on 04 October 2015. A Marketing Authorisation was granted in the UK to

Winthrop Pharmaceuticals UK Limited (trading as Zentiva) on 22 October 2015.

The full PAR for Valganciclovir tablets follows this summary.

For more information about treatment with Valganciclovir tablets, read the package leaflet, or contact

your doctor or pharmacist.

This summary was last updated in December 2015.

Valganciclovir 450mg film-coated tablets

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4

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 5

Quality aspects

Page 6

Non-clinical aspects

Page 13

Clinical aspects

Page 13

User consultation

Page 15

Overall conclusion, benefit/risk assessment and

recommendation

Page 15

Annex 1 - Table of content of the PAR update for MRP and DCP

Page 17

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5

Scientific discussion

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Member States considered that the

application for Valganciclovir 450mg film-coated tablets (PL 17780/0688; UK/H/5641/001/DC) could

be approved. This product is a prescription-only medicine (POM) indicated for the:

induction and maintenance treatment of cytomegalovirus (CMV) retinitis in adult patients with

acquired immunodeficiency syndrome (AIDS);

prevention of CMV disease in CMV-negative adults and children ( aged from birth to 18 years) who

have received a solid organ transplant from a CMV-positive donor.

The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference

Member State (RMS), and the Czech Republic, France, Romania and Poland as Concerned Member

States (CMS). The application was submitted under Article 10(1) of Directive 2001/83/EC, as amended,

claiming to be a generic medicinal product of Valcyte 450mg film-coated tablets (Roche Nederland

B.V., the Netherlands), which were first approved in the Netherlands on 20 September 2001. The

corresponding reference product in the UK is Valcyte 450mg film-coated tablets (PL 00031/0599),

which were authorised in the UK on 25 April 2002, following an incoming Mutual Recognition

Procedure (NL/H/0323/01/MR).

The active ingredient, valganciclovir is the L-valyl ester of ganciclovir. As a prodrug, after oral

administration, it is rapidly converted to ganciclovir. Ganciclovir is a synthetic analog of guanine and is

effective against human cytomegalovirus (CMV) infections. The advantage of valganciclovir is the

ability to attain

in vivo

exposure similar to intravenous (i.v.) ganciclovir and higher than oral ganciclovir

capsules. Valganciclovir is indicated for the induction and maintenance treatment of CMV retinitis in

patients with acquired immunodeficiency syndrome (AIDS) and for the prevention of CMV disease in

CMV-negative patients who have received a solid organ transplant from a CMV-positive donor.

One single-dose, bioequivalence study was submitted to support this application, comparing the

applicant’s test product Valganciclovir 450 mg Film-coated Tablets and the reference product Valcyte

450mg film-coated tablets (Roche Pharma AG, Germany) under fed conditions. The Applicant states

that the study was conducted in accordance with Good Clinical Practice.

With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted,

which is acceptable given that the application was based on being a generic medicinal product of an

originator product that has been in clinical use for over 10 years.

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place at all sites responsible for the manufacture, assembly and batch release of this product. For

manufacturing sites within the Community, the RMS has accepted satisfactory declarations that

acceptable standards of GMP are in place at those sites.

The RMS and CMS considered that the applications could be approved at the end of procedure

(Day 210) on 04 October 2015. After a subsequent national phase, a licence was granted in the UK to

Winthrop Pharmaceuticals UK Limited (trading as Zentiva) on 22 October 2015.

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6

II.

QUALITY ASPECTS

II.1

INTRODUCTION

The submitted documentation concerning the proposed product is of sufficient quality and meets the

current EU regulatory requirements.

The quality overall summary has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical aspects of the dossier.

Each film-coated tablet contains 496.3mg of valganciclovir hydrochloride equivalent to 450mg of

valganciclovir (as free base).

The product also contains the pharmaceutical excipients, povidone (K30), crospovidone (Type A),

microcrystalline cellulose (Vivapur Type 101), stearic acid and Opadry Pink 15B24005 ( which consists

of the constituents hypromellose (3cP, 6 cP), titanium dioxide (E171), macrogol MW 400/PEG, iron

oxide red (E172) and polysorbate 80). Appropriate justification for the inclusion of each excipient has

been provided.

With the exception of Opadry Pink 15B24005 and its constituents, all the excipients comply with their

respective European Pharmacopoeia monographs. Opadry Pink 15B24005 is controlled to a suitable

in-house specification. Hypromellose (3cP, 6 cP) and titanium dioxide (E171) comply with their

respective United States Pharmacopoeial monographs. Macrogol MW 400/PEG, iron oxide red (E172)

and polysorbate 80 comply with their respective National Formulary specifications. The specification for

iron oxide red (E172) is also in compliance with current EU Directives concerning the use of colouring

agents.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

The finished product is packaged in high density polyethylene (HDPE) bottles with child resistant,

tamper evident polypropylene (PP) screw caps with induction heat sealing (with aluminum foil).

Valganciclovir 450mg film-coated tablets are available in pack size of one bottle containing

60 film-coated tablets.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2

DRUG SUBSTANCE

rINN:

Valganciclovir hydrochloride

Chemical name(s):

L-Valine, 2-[2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl] methoxy]-3-

hydroxypropyl ester, , monohydrochloride

Structure:

Molecular formula:

390.83

Appearance:

A white to off-white powder

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UK/H/5641//001/DC

7

Solubility

Very slightly soluble in alcohol and practically insoluble in isopropyl alcohol, in

acetone, in hexane, and in ethyl acetate

Valganciclovir hydrochloride is not the subject of a European Pharmacopoeia monograph.

Synthesis of the active substance from the designated starting materials has been adequately described

and appropriate in-process controls and intermediate specifications are applied. Satisfactory

specification tests are in place for all starting materials and reagents and these are supported by relevant

Certificates of Analysis. Appropriate proof-of-structure data have been supplied. All potential known

impurities have been identified and characterised.

An appropriate specification is provided for the active substance. Analytical methods have been

appropriately validated and are satisfactory for ensuring compliance with the relevant specifications.

Batch analysis data are provided that comply with the proposed specification.

Satisfactory Certificates of Analysis have been provided for all working standards.

Suitable specifications have been provided for all packaging used. The primary packaging has been

shown to comply with current guidelines concerning contact with foodstuff.

Appropriate stability data have been generated to support a suitable retest period when stored in the

proposed packaging.

II.3

MEDICINAL PRODUCT

Pharmaceutical Development

The objective of the development programme was to formulate a safe, efficacious, stable product that

could be considered a generic medicinal product of the innovator product Valcyte 450mg film-coated

tablets (Roche).

Suitable pharmaceutical development data have been provided for this application.

Comparative

in-vitro

dissolution profiles

have been provided for this product and the reference product.

Manufacturing Process

A satisfactory batch formula has been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. The manufacturing process has been validated with

pilot-scale batches and has shown satisfactory results. The Marketing Authorisation Holder has

committed to performing process validation studies on the first three full-scale production batches.

Control of Finished Product

The finished product specification is acceptable. Test methods have been described and have been

validated adequately. Batch data have been provided and comply with the release specifications.

Certificates of Analysis have been provided for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of

finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 24 months

has been accepted. There are no special storage conditions required for the product.

Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

8

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the

bioequivalence study. The bioequivalence study is discussed in Section III.3, Clinical Aspects.

II.4

Discussion on chemical, pharmaceutical and biological aspects

It is recommended that a Marketing Authorisation is granted for Valganciclovir 450mg film-coated

tablets.

II.5

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

Labels

The SmPC, PIL and labelling are satisfactory and, where appropriate, in line with current guidance.

In accordance with Directive 2010/84/EU, the current version of the SmPC and PILs are available on the

MHRA website.

The current labelling is presented below:

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

9

The MAH has submitted a text version only and has committed to submitting mock-up livery to

the relevant regulatory authorities for approval before packs are marketed.

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

10

Valganciclovir 450mg film-coated tablets

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11

Valganciclovir 450mg film-coated tablets

UK/H/5641//001/DC

12

Valganciclovir 450mg film-coated tablets

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13

III.

NON-CLINICAL ASPECTS

III.1

Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of valganciclovir are

well-known, no new non-clinical data are required and none have been provided.

III.2

Pharmacology

Not applicable, see Section III.1 Introduction, above.

III.3

Pharmacokinetics

Not applicable, see Section III.1 Introduction, above.

III.4

Toxicology

Not applicable, see Section III.1 Introduction, above.

III.5

Ecotoxicity/Environmental Risk Assessment (ERA)

Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As

the application is for a generic version of an already authorised product, it is not expected that

environmental exposure will increase following approval of the Marketing Authorisation for the

proposed product.

III.6

Discussion of the non-clinical aspects

The grant of a Marketing Authorisation is recommended.

IV.

CLINICAL ASPECTS

IV.1

Introduction.

The clinical pharmacology of valganciclovir is well-known. With the exception of data generated from

the bioequivalence study detailed below, no new pharmacodynamic or pharmacokinetic data are

provided or required for this application.

In accordance with the regulatory requirements CPMP/EWP/QWP/1401/98 Rev 1/Corr, Guideline on

the Investigation of Bioequivalence, the Marketing Authorisation Holder submitted a bioequivalence

study to support the application, comparing the applicant’s test Valganciclovir 450 mg tablets (Zentiva,

the Czech Republic) with the reference product Valcyte 450mg film-coated tablets (Roche Pharma AG,

Germany) under fed conditions.

IV.2

Pharmacokinetics

The clinical pharmacokinetic properties of valganciclovir are well-known. With the exception of data

from the bioequivalence study detailed below, no new pharmacokinetic data are provided or required for

this application.

In support of the application, the Marketing Authorisation Holder submitted the following

bioequivalence study:

An open-label, single-dose, block randomised, two-sequence, two-period, crossover study

comparing the applicant’s test product Valganciclovir 450 mg tablets (Zentiva, the Czech

Republic) and the reference product Valcyte 450mg film-coated tablets (Roche Pharma AG,

Germany) in male and infertile female healthy adult subjects under fed conditions.

The subjects were fasted for at least 10 hours prior to a standard high-calorie, high-fat breakfast. The

subjects were administered one tablet (450 mg) of either the test or the reference product with about

240 ml of water, 30 minutes after the start of breakfast. Blood samples were collected before and up to

Valganciclovir 450mg film-coated tablets

UK/H/5641/001/DC

14

and including 24 hours after each administration. The washout period between the treatment phases was

7 days. The pharmacokinetic results are presented below for

90% confidence intervals valganciclovir mean treatment test/reference ratios

Test name

Parameter

Test value

(T/R)

Lower

90% CL

Upper 90%

CL

Classic 90% CI

(0-t)

100.351

98.028

102.729

Classic 90% CI

92.977

83.330

103.740

confidence limit

maximum analyte concentration over the sampling period

area under the analyte concentration versus time curve from time zero to t hours, as calculated by the linear trapezoidal method

Ratios and 90% CI calculated from ln-transformed data

Conclusion

The 90% confidence intervals of the test/reference ratio for AUC

, and C

lie within the acceptable

limits of 80.00% to 125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence

(CPMP/EWP/QWP/1401/98 Rev 1/Corr**).Thus, the data support the claim that the applicant’s test

product is bioequivalent to the reference Valcyte 450mg film-coated tablets (Roche Pharma AG,

Germany) under fed conditions.

IV.3

Pharmacodynamics

The clinical pharmacodynamic properties of valganciclovir are well-known. No new pharmacodynamics

data were submitted and none are required for this type of application.

IV.4

Clinical Efficacy

The clinical efficacy of valganciclovir is well-known. No new efficacy data are presented for this type of

application.

IV.5

Clinical Safety

With the exception of the safety data generated during the bioequivalence study no new safety data were

submitted and none are required for this type of application. The safety profile of valganciclovir is

well-known. No new or unexpected safety issues were raised during the bioequivalence study.

IV.6

Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive

2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to

identify, characterise, prevent or minimise risks relating to Valganciclovir 450 mg Film-coated Tablets.

The following table lists the summary of safety concerns which have been identified:

Valganciclovir 450mg film-coated tablets

UK/H/5641/001/DC

15

Appropriate pharmacovigilance and risk minimisation activities have been addressed.

IV.7

Discussion of the clinical aspects

is

recommended that a Marketing Authorisation is granted for Valganciclovir 450mg film-coated

tablets.

V.

USER CONSULTATION

A package leaflet has been evaluated via a user consultation study in accordance with the requirements

of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The language used for the purpose of

user testing the package information leaflet (PIL) was English.

The results show that the package leaflet meets the criteria for readability as set out in the Guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

QUALITY

The important quality characteristics of Valganciclovir 450mg film-coated tablets are well-defined and

controlled. The specifications and batch analytical results indicate consistency from batch to batch.

There are no outstanding quality issues that would have a negative impact on the benefit/risk balance.

NON-CLINICAL

No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology

of valganciclovir are well-known, no additional data were required.

No new non-clinical data were submitted and none are required for this type of application.

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16

EFFICACY

With the exception of the bioequivalence study, no new data were submitted and none are required for

this type of application.

Bioequivalence has been demonstrated between the applicant’s product and the reference product

Valcyte 450mg film-coated tablets (Roche Pharma AG, Germany).

SAFETY

With the exception of the safety data from the bioequivalence study, no new data were submitted and

none are required for an application of this type. As the safety profile of valganciclovir is well known,

no additional data were required. No new or unexpected safety concerns arose from the bioequivalence

study.

PRODUCT LITERATURE

The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product, where

appropriate and in line with current guidance.

BENEFIT/RISK ASSESSMENT

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. Extensive clinical experience with valganciclovir is considered to have demonstrated the

therapeutic value of the compound. The benefit/risk balance is therefore considered to be positive.

RECOMMENDATION

The grant of a Marketing Authorisation is recommended.

Valganciclovir 450mg film-coated tablets

UK/H/5641/001/DC

17

Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

Scope

Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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