Valtrex™ 500 mg film-coated tablets

Update Section 4 - Possible side effects to add: an inflammation of the kidneys (Tubulointerstitial nephritis) with a frequency "not know"

Update Section 6 with the new date of revision.

Update Section 4.8 - Undesirable effects to add: "Tubulointerstitial nephritis" with frequency "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

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

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.

New text highlighted in Red:

4.4       Special Warnings and Special Precautions for Use

Hydration status: Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.

Use in patients with renal impairment and in elderly patients: Aciclovir is eliminated by renal clearance, therefore the dose of valaciclovir must be reduced in patients with renal impairment (see section 4.2). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see section 4.8)

 Valtrex have not been conducted in liver transplantation; however high dose aciclovir prophylaxis has been shown to reduce CMV infection and disease.

Use in genital herpes: Suppressive therapy with valaciclovir reduces the risk of transmitting genital herpes.  It does not cure genital herpes or completely eliminate the risk of transmission.  In addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.

4.6       Pregnancy and Lactation

Teratogenicity:

Valaciclovir was not teratogenic in rats or rabbits.  Valaciclovir is almost completely metabolised to aciclovir.  Subcutaneous administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits.  In additional studies in rats, foetal abnormalities were observed at subcutaneous doses that produced plasma levels of 100 g/ml and maternal toxicity.

Fertility:

Valaciclovir did not affect fertility in male or female rats dosed by the oral route.

Pregnancy:

There are limited data on the use of Valtrex in pregnancy. Valtrex should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.

Pregnancy registries have documented the pregnancy outcomes in women exposed to valaciclovir or to any formulation of aciclovir (the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy), respectively, were obtained from women prospectively registered.  The findings of the aciclovir pregnancy registry have not shown an increase in the number of birth defects amongst aciclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.  Given the small number of women enrolled into the valaciclovir pregnancy registry, reliable and definitive conclusions could not be reached regarding the safety of valaciclovir in pregnancy.

4.8       Undesirable Effects

Renal and urinary disorders

Rare:                *Renal impairment.

Very rare:        *Acute renal failure, renal pain

Renal pain may be associated with renal failure.