Update section 6.5 to remove pack size 20.

Update date of revision of the text

Section 6 - Delete a pack size 20 and update revision date

Update section 4 - Possible side effects to add: Inflammation of the kidneys (Tubulointerstitial nephritis) with a frequency "not known".

Update section 6 with the new date of revision.

Change Section 4.8 - Undesirable effects to add: "Tubulointerstitial nephritis" with frequency as "not known".

Update section 10 - Date of revision of the text

4.2, 4.6., 5.1 and 5.3 - admin updates
4.4 and 4.8 - DRESS update

4.2, 4.6., 5.1 and 5.3 - admin updates
4.4 and 4.8 - DRESS update

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Antivirals for systemic use.

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB11.

6.       PHARMACEUTICAL PARTICULARS

6.1         List of excipients

Tablet core

Microcrystalline cellulose

Crospovidone

Povidone

Magnesium stearate

Silica colloidal anhydrousColloidal silicon dioxide

Film coat

Hypromellose

Titanium dioxide

Polyethylene glycolMacrogol 400Macrogol

Polysorbate 80 (500 and 1000 mg tablets only)

Carnauba wax

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]2011-12-15

10.     DATE OF REVISION OF THE TEXT

2012-01-202011-07-12

3.              pharmaceutical form

Film-coated tablets.

White film-coated tablet, biconvex, elongated tablet with a white to off-white core,. Biconvex, elongated, unscored, marked branded “GX CE7” in blue ink on one side by engraving.

4.                            clinical particulars

4.1            Therapeutic Indications

Varicella zoster virus (VZV) infections – herpes zoster

Valtrex is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults (see section 4.4).

Valtrex is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression (see section 4.4).

Herpes simplex virus (HSV) infections

Valtrex is indicated

·         for the treatment and suppression of HSV infections of the skin and mucous membranes including

o   treatment of first-episode of genital herpes in immunocompetent adults and adolescents and in immunocompromised adults

o   treatment of recurrences of genital herpes in immunocompetent adults and adolescents, and in immunocompromised adults

o   Treatment and suppression of recurrent ocular HSV infections (see section 4.4)

o   suppression of recurrent genital herpes in immunocompetent adults and adolescents and in immunocompromised adults.

·         Treatment and suppression of recurrent ocular HSV infections (see section 4.4)

Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection (see section 5.1).

Cytomegalovirus (CMV) infections:

Valtrex is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents (see section 4.4).

4.8                        Undesirable Effects

The most common adverse reactions (ARs) reported in at least one indication by patients treated with Valtrex in clinical trials were headache and nausea. More serious ARs such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure and neurological disorders are discussed in greater detail in other sections of the label.

Undesirable effects are listed below by body system organ class and by frequency.

The following frequency categories are used for classification of adverse effects:

Very common             ³ 1/10,

Common                     ³ 1/100 and < 1/10,

Uncommon                 ³ 1/1,000 and < 1/100,

Rare                            ³ 1/10,000 and < 1/1,000,

Very rare                     < 1/10,000.

Clinical trial data have been used to assign frequency categories to ARs if, in the trials, there was evidence of an association with valaciclovir.

For ARs identified from postmarketing experience, but not observed in clinical trials, the most conservative value of point estimate (‘rule of three’) has been used to assign the AR frequency category. For ARs identified as associated with valaciclovir from post-marketing experience, and observed in clinical trials, study incidence has been used to assign the AR frequency category. The clinical trial safety database is based on 5855 subjects to valaciclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment/suppression of genital herpes & treatment of cold sores).

Clinical Trial Data

Nervous system disorders

Very common:                 Headache.

Gastrointestinal disorders

Common:         Nausea.

 

Post Marketing Data

 

Blood and lymphatic system disorders

Uncommon:     Leucopenia, thrombocytopenia.

Leucopenia is mainly reported in immunocompromised patients.

 

Immune system disorders

Rare:    Anaphylaxis.

 

Psychiatric and nervous system disorders

Common:        Dizziness

Uncommon:    confusion, hallucinations, decreased consciousness, tremor, agitation.

Rare:                ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium.

 

Neurological disorders, sometimes severe, may be linked to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see section 4.4). In organ transplant patients receiving high doses (8000 mg daily) of Valtrex for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

 

Respiratory, thoracic and mediastinal disorders

Uncommon:     Dyspnoea.

 

Gastrointestinal disorders

Common:        vomiting, diarrhoea

Uncommon:    Abdominal discomfort

 

Hepato-biliary disorders

Uncommon:     Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).

 

Skin and subcutaneous tissue disorders

Common:         Rashes including photosensitivity, pruritus

Uncommon:     Urticaria,

Rare:                angioedema.

 

Renal and urinary disorders

Uncommon:                 Renal Pain, haematuria (often associated with other renal events).

Rare:                            Renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).

Renal pain may be associated with renal failure.

 

Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).

 

 

Additional information on special populations

There have been reports of renal insufficiency, microangiopathic haemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8000 mg daily) of valaciclovir for prolonged periods in clinical trials. These findings have been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

There are changes throughout the SPC but the most significant are:

·         The doses of Valtrex should be reduced in patients with impaired kidney function.

·         The addition of the indication for treatment of herpes zoster and the expansion of the indication to include treatment of ophtalmic zoster, treatment and supression of herpes simplex virus in immunocompetent adults and adolescents and in immunocompromised adults, and treatment and suppression of recurrent ocular HSV infections.

·         The introduction of dose instructions for treatment of herpes zoster and the revision of dose instructions in HSV infections of the skin and mucous membranes in immunocompetent and immunocompromised patients, including the addition of a dose instruction for the treatment of herpes labialis (cold sores).

·         The sections regarding warnings and precautions, interactions, fertility, pregnancy and lactation, side effects, overdose and pharmacological properties have also been revised further to the review of updated clinical data.