Valatrex 250 mg, 500 mg FC tablets

Treatment to start as soon as possible within 24 hours VALATREX is indicated for the:

• Treatment of herpes zoster (shingles). VALATREX reduces the duration of zoster-associated pain, which includes acute and post-herpetic neuralgia, thus accelerating resolution of pain. VALATREX also reduces the proportion of patients with zoster-associated pain.
• Episodic treatment of recurrent genital herpes in immunocompetent adult patients. There is no data on the effectiveness of VALATREX when initiated more than 24 hours after the onset of signs and symptoms.
• Prevention (suppression) of recurrent herpes simplex infection of the skin and mucous membrane of the ano-genital area.
• Prophylaxis of cytomegalovirus (CMV) infection, CMV disease and other herpes virus infections following organ transplantation, where a special risk exists.

Dosage in adults:

For treatment of Herpes zoster: 1000 mg of VALATREX to be taken three times per day for seven days.

Recurrent genital herpes: The recommended dosage for the treatment of recurrent genital herpes is 500 mg twice daily for 5 days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately the first signs or symptoms appear. There are no data on the effectiveness of VALATREX when initiated more than 24 hours after the onset of signs and symptoms.

Prevention (suppression) of recurrences of herpes simplex infection:

• Immunocompetent patients: 500 mg to be taken once daily. Some patients with very frequent recurrences (e.g. 10 or more per year) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily).
• lmmunocompromised patients: 500 mg twice daily.

Prophylaxis of cytomegalovirus infection (CMV) and disease: Adults and adolescents (from 12 years of age): 2000 mg to be taken four times a day. Dosing should be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see u201cDosage in renal impairmentu201d). The duration of treatment will usually be 90 days, but may need to be extended in high risk patients.

Dosage in children: No data are available.

Dosage in the elderly: Dosage modification is not required unless renal function is impaired (see u201cDosage in renal impairmentu201d). Adequate hydration should be maintained.

Dosage in renal impairment: The dose of VALATREX should be modified as follows in patients with significantly impaired renal function:

Herpes Zoster

Creatinine Clearance VALATREX dose

• 15 to 30 m u2113 /min 1000 mg twice a day
• < 15 m u2113 /min 1000 mg once a day

Recurrent Genital Herpes

Creatinine Clearance VALATREX dose

• > 15 m u2113 /min 500 mg twice daily
• 0 to 15 m u2113 /min 500 mg once daily

Prevention of Recurrences

Creatinine Clearance VALATREX dose

• Immunocompetent Immunocompromised
• 15 to 30 m u2113 /min No dosage adjustment required
• < 15 m u2113 /min 250 mg once daily 500 mg once daily

In patients on haemodialysis the VALATREX dose recommended for patients with a creatinine clearance of less than 15 mu2113/min should be used, but the dose should be administered after the haemodialysis has been performed.

Dosage in CMV prophylaxis: The dosage of VALATREX should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine Clearance VALATREX

• > 75 m u2113 /min 2 000 mg four times daily
• 50 to < 75 m u2113 /min 1 500 mg four times daily
• 25 to < 50 m u2113 /min 1 500 mg three times daily
• 10 to < 25 m u2113 /min 1 500 mg twice daily
• < 10 m u2113 /min or dialysis ** 1 500 mg once daily

** In patients on haemodialysis, the VALATREX dosage should be administered after the haemodialysis has been performed. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The VALATREX dosage should be adjusted accordingly.

Dosage in hepatic impairment: Dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment; however, clinical experience is limited. For higher doses recommended for CMV prophylaxis (see section 4.4).

VALATREX is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or any component of the formulations. Pregnancy and lactation (see section 4.6).

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).

Use of higher doses of valaciclovir in hepatic impairment and liver transplantation: There are no data available on the use of higher doses of valaciclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valaciclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients.

Use for zoster treatment: Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.

Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy. Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Transmission of genital herpes: Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.

Use in ocular HSV infections: Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.

Use in CMV infections: Data on the efficacy of valaciclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir. High dose valaciclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications (see section 4.8). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see section 4.2).

Skin reactions: There is a risk of Acute generalized exanthematous pustulosis (AGEP) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with the use of acyclovir and valacyclovir containing medicines. DRESS and AGEP are considered serious cutaneous adverse reactions (SCARs) which are unpredictable and present an important risk to patients. Therefore, if a patient develops reactions classified as SCARs during VALATREX use, treatment should be withdrawn immediately, and an alternative treatment considered (as appropriate), and treatment with these medicines must not be restarted for the patient at any time.

The combination of valaciclovir with nephrotoxic medicinal products should be made with caution, especially in subjects with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, and tacrolimus.

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Following 1000 mg valaciclovir, cimetidine and probenecid reduce aciclovir renal clearance and increase the AUC of aciclovir by about 25 % and 45 %, respectively, by inhibition of the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increased aciclovir AUC by about 65 %. Other medicinal products (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, valaciclovir administration may increase plasma concentrations of the concurrently administered substance.

In patients receiving higher aciclovir exposures from valaciclovir (e.g., at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with drugs which inhibit active renal tubular secretion. Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered. No changes in peak concentrations or AUCs are observed with co-administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience with the use of this combination.

Safety in pregnancy and during lactation has not been established.

No studies on the effects on the ability to drive and use machines have been performed. Undesirable effects such as lethargy and somnolence are possible after taking VALATREX. If affected, patients should not drive or operate machinery.

Valaciclovir was well tolerated when used for the treatment of herpes zoster or herpes simplex in clinical trials.

Blood and lymphatic system disorders: Less frequent: Leucopenia, thrombocytopenia.

Immune system disorders: Less frequent: Anaphylaxis.

Psychiatric and nervous system disorders: Frequent: Headache. Less frequent: Dizziness, confusion, hallucinations (particularly in organ transplant patients receiving high doses of VALATREX for CMV prophylaxis), lethargy, somnolence, decreased consciousness, agitation, tremors, ataxia, dysarthria, psychotic symptoms, delirium, convulsions, encephalopathy and coma. 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 Valatrex for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

Respiratory, thoracic and mediastinal disorders: Less frequent: Dyspnoea.

Gastrointestinal disorders: Frequent: Vomiting, diarrhoea. Less frequent: Abdominal discomfort.

Hepato-biliary disorders: Less frequent: Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).

Skin and subcutaneous tissue disorders: Frequent: Skin rashes, including photosensitivity, pruritus. Less frequent: Urticaria, angioedema. Frequency unknown: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Acute generalized exanthematous pustulosis (AGEP)

Renal and urinary disorders: Less frequent: Renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses). Renal pain, haematuria (often associated with other renal events). 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 also been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms and Signs: Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Treatment: Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.