Mylan Valaciclovir 250 mg, 500 mg FC tablet

MYLAN VALACICLOVIR is used in the treatment of:

• Herpes Zoster (shingles) infections. It reduces the duration of zoster-associated pain, which includes acute and post-herpetic neuralgia, thus accelerating resolution of pain.
• Episodic treatment of recurrent genital herpes in immunocompetent adult patients.
• Prevention/suppression of recurrent herpes simplex infections of the skin and mucous membranes of the ano-genital area.
• Prophylaxis of cytomegalovirus (CMV) infection.
• Prophylaxis of cytomegalovirus (CMV) and other herpes infections following organ transplant where a special risk exists.

Posology

Treatment of Herpes Zoster infections:

Adults: 1000 mg three times a day for 7 days

Recurrent genital herpes:

Immunocompetent patients: 500 mg twice daily for 5 days beginning as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately when the first symptoms appear. There are not data on efficacy when treatment was initiated after 24 hours after the onset of symptoms.

Prevention or suppression of recurrent Herpes simplex infections:

Immunocompetent patients: 500 mg once daily. If more than 10 episodes occur per year, administer 250 mg twice daily.

Immunocompromised patients: 500 mg twice daily.

CMV infection prophylaxis:

Adults and adolescents 12 years and older: Initiate therapy as soon as possible.

Post-transplant: 2000 mg four times daily for usually 90 days. The duration of treatment may have to be extended in high-risk patients. Modify the dosage in significant renal impairment.

Special populations

Elderly population: Dose modification is not required unless renal function is impaired. Adequate hydration must be ensured.

Renal impairment: The dose of MYLAN VALACICLOVIR should be modified as follows in patients with significantly impaired renal function:

Herpes Zoster

Creatinine clearance MYLAN VALACICLOVIR dose

15-30 ml/min 1000 mg twice daily

< 15 ml/min 1000 mg once a day

Recurrent Genital herpes

Creatinine clearance MYLAN VALACICLOVIR dose

> 15 ml/min 500 mg twice daily

0 - 15 ml/min 500 mg once daily

Prevention of recurrences

Creatinine clearance MYLAN VALACICLOVIR dose

Immunocompetent Immunocompromised

15 u2013 30 ml/min No dosage adjustment required

< 15 ml/min 250 mg once daily 500 mg once daily

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

CMV prophylaxis

Creatinine clearance MYLAN VALACICLOVIR dose

> 75 ml/min 2000 mg four times daily

50 to 75 ml/min 1500 mg four times daily

25 to 50 ml/min 1500 mg three times daily

10 to 25 ml/min 1500 mg twice daily

< 10 ml/min or dialysis* 1500 mg once a day

* In patients on haemodialysis, the MYLAN VALACICLOVIR dose should be administered after the haemodialysis have 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 MYLAN VALACICLOVIR dose should be adjusted accordingly.

Method of administration

For oral use.

• Hypersensitivity to valaciclovir, aciclovir or any of the other ingredients.
• Safety in pregnancy and lactation has not been established.

Thrombotic, thrombocytopenic purpura/haemolytic uraemic syndrome, in some cases resulting in death, has been reported in patients with advanced HIV disease and also in bone marrow transplant and renal transplant patients.

Central nervous system (CNS) adverse reactions including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy have been reported. Elderly patients are more likely to be prone to these adverse reactions. MYLAN VALACICLOVIR should be discontinued if CNS adverse reactions occur.

Drug reaction with eosinophilia and systemic symptoms (DRESS) DRESS, which can be life-threatening or fatal, has been reported in associate with valaciclovir treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of DRESS appear, valaciclovir should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed DRESS with the use of valaciclovir, treatment with valaciclovir must not be restarted in this patient at any time.

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. Cases of acute renal failure have been reported in elderly patients, with or without reduced renal function, patients with underlying renal disease receiving higher than recommended doses, patients receiving other nephrotoxic medicines and patients without adequate hydration. All patients should be adequately hydrated.

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 (see section 4.8).

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. However, 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.

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 Published 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, as contained in MYLAN 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 central nervous system 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).

• The combination of valaciclovir, as contained in MYLAN VALACICLOVIR with nephrotoxic medicines should be used with caution, especially in patients 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.
• Although no clinically significant interactions have been reported, any medicine which is excreted via renal tubular secretion may compete, and thus interact, with MYLAN VALACICLOVIR.
• Cimetidine and probenecid have been shown to decrease the renal excretion of aciclovir and to increase the area under the curve (AUC) of aciclovir. No significant increase in toxicity was noted when zidovudine was given together with aciclovir.
• In patients receiving higher aciclovir exposures from valaciclovir, as contained in MYLAN VALACICLOVIR (e.g., at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with medicines which inhibit active renal tubular secretion.
• Increases in plasma AUCu2019s of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant medicine used in transplant patients, have been shown when co-administered.
• Care should be taken when high-dose MYLAN VALACICLOVIR is administered with other medicines that affect other aspects of renal physiology (e.g. ciclosporin, tacrolimus).
• Caution is required during concurrent administration with medicines which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both medicines or their metabolites.
• Other medicines (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 medicine.

Pregnancy Safety in pregnancy has not been established. Foetal abnormalities were observed in rats.

Breastfeeding Safety in lactation has not been established.

Fertility No data.

MYLAN VALACICLOVIR has been reported to cause dizziness and confusion. Patients should be cautioned against driving or operating machinery until it is established how they react to MYLAN VALACICLOVIR.

Summary of the safety profile The most common adverse reactions (ARs) reported are headache and nausea. For more information on serious side effects such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure, neurological disorders and DRESS, see section 4.4.

Tabulated list of adverse reactions

Body System Undesirable effect Frequent Less frequent Frequency not known

Blood and the lymphatic system disorders: Aplastic anaemia, thrombocytopenia, leukopenia, neutropenia, leukocytoclastic vasculitis.

Immune system disorders: Hypersensitivity reactions, angioedema, anaphylaxis.

Psychiatric disorders: Mania, psychosis including auditory and visual hallucinations, aggressive behaviour, delirium, psychotic symptoms.

Nervous system disorders: Headache. In patients treated with high doses for CMV prophylaxis, Reversible neurological reactions (confusion, fatigue and dizziness) may occur in patients with renal impairment. Dizziness, agitation, ataxia, coma, confusion, decreased consciousness, tremor, dysarthria, convulsions, encephalopathy.

Eye disorders: Visual abnormalities.

Cardiac disorders: Tachycardia.

Vascular disorders: Hypertension.

Respiratory, thoracic and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Nausea, diarrhoea. Gastro-intestinal disturbances, vomiting, abdominal discomfort.

Hepato-biliary disorders: Hepatitis, jaundice, abnormal liver function tests.

Skin and subcutaneous tissue disorders: Rash, erythema multiforme, photosensitivity, alopecia, Stevens-Johnson syndrome, toxic epidermal necrosis, urticaria, pruritus, angioedema. Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4)

Musculoskeletal, connective tissue and bone disorders: Arthralgia.

Renal and urinary disorders: Renal pain, haematuria, renal impairment, renal insufficiency, increased serum creatinine, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).

Reproductive system and breast disorders: Dysmenorrhoea.

Description of selected adverse reactions u2022 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).

u2022 Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA on the SAHPRA website at: https://medsafety.sahpra.org.za/#download1 , via email at: [email protected] or via telephone at: 0125010311

• In overdose, side effects can be precipitated and/or be of increased severity ( see section 4.8).
• There are no data available on overdosage.
• In animals, large doses caused obstructive uropathy and crystalluria.
• Treatment is symptomatic and supportive.
• Haemodialysis, if required, enhances the removal of MYLAN VALACICLOVIR.