Olcican 450 450 mg FC Tablet

OLCICAN 450 MG is indicated for:

• The treatment of cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome (AIDS) patients.
• The prevention of CMV disease in solid organ transplant patients who are at risk i.e., donor seropositive and recipient seronegative.

Posology

Strict adherence to dosage recommendations is essential to avoid overdose. The bioavailability of ganciclovir from OLCICAN 450 MG is up to 10-fold higher than from ganciclovir capsules, therefore the dosage and administration of OLCICAN 450 MG tablets should be closely followed.

Standard dosage in adults

Induction treatment of CMV retinitis

For patients with active CMV retinitis, the recommended dose is 900 mg OLCICAN 450 MG twice a day for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity.

Maintenance treatment of CMV retinitis

Following induction treatment, or in patients with inactive CMV retinitis, the recommended dose is 900 mg OLCICAN 450 MG once daily. Patients whose retinitis worsens may repeat induction treatment; however, consideration should be given to the possibility of viral drug resistance.

Prevention of CMV disease in solid organ transplantation

For kidney transplant patients, the recommended dose is 900 mg once daily depending on creatinine clearance, starting within 10 days of transplantation until 200 days post-transplantation. For patients who have received a solid organ transplant other than the kidney, the recommended dose is 900 mg once daily, starting within 10 days of transplantation until 100 days post transplantation.

Special Populations

Patients with renal impairment

Serum creatinine levels or creatinine clearance should be monitored carefully. Dosage adjustment is required for adult patients based on creatinine clearance, as shown in tables 2 and 3 below. Creatinine clearance (mL u2113 /min) is calculated from serum creatinine by the following formulae:

CLCR (mL/min) = (140 u2013 age) x (Wt [kg]) x constant* / SCR [u03bcmol/L]

* Constant = 1,23 for males and 1,04 for females (0,85 x 1,23 = 1,04)

The South African Renal Society recommends simplifying the above formula by omitting the constant of 1,23 for males:

CLCR (mL/min) = (140 u2013 age) x (Wt [kg]) x 0,85 (if female) / SCR [u03bcmol/L]

OLCICAN 450 MG dose for renally impaired patients

Patients undergoing haemodialysis

Dosage adjustment is necessary for patients on haemodialysis (CrCl < 10 mL/min).

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

Patients with severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with OLCICAN 450 MG (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/u03bcL or the platelet count is less than 25 000/u03bcL or the haemoglobin is less than 8 g/dL (see section 4.4).

Elderly

Safety and efficacy have not been established.

Paediatric patients

Safety and efficacy have not been established in adequate and well-controlled clinical studies.

Method of administration

OLCICAN 450 MG is administered orally and should be taken with food. The tablets should not be broken or crushed. Since OLCICAN 450 MG 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.

OLCICAN 450 MG is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any excipient of the product (see section 6.1). Due to the similarity of the chemical structure of OLCICAN 450 MG and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these medicines is possible. OLCICAN 450 MG is contraindicated during breastfeeding (see section 4.6).

Cross-hypersensitivity

Caution should therefore be used when prescribing OLCICAN 450 MG 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, carcinogenic, and a suppressor of fertility. OLCICAN 450 MG should therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see section 5.3). Based on clinical and nonclinical studies it is also considered likely that OLCICAN 450 MG causes temporary or permanent inhibition of spermatogenesis. Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term.

Women of childbearing potential must be advised to use effective contraception during treatment. Male patients should be advised to practice barrier contraception during, and for at least 90 days following treatment with OLCICAN 450 MG.

Myelosuppression

Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with valganciclovir as contained in OLCICAN 450 MG (and ganciclovir). Severe thrombocytopenia may be associated with potentially life-threatening bleeding. Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/u03bcL, or the platelet count is less than 25 000/u03bcL, or the haemoglobin level is less than 8 g/dL. Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/u03bcL, or the platelet count is less than 25000/u03bcL, or the haemoglobin level is less than 8 g/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). OLCICAN 450 MG 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 be monitored during therapy. In patients with 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). Safety and efficacy in children have not been established in adequate and well-controlled clinical studies (see section 4.2).

The bioavailability of ganciclovir from OLCICAN 450 MG is up to 10-fold higher than from ganciclovir capsules. OLCICAN 450 MG cannot be substituted for ganciclovir capsules on a one-to-one basis. 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. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of OLCICAN 450 MG tablets (see section 4.2). In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see section 4.2). For patients on haemodialysis (CrCl < 10 mL/min), OLCICAN film-coated tablets should not be used.

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. OLCICAN 450 MG should not be used concomitantly with imipenem-cilastatin unless the potential benefit outweighs the potential risks (see section 4.5). Zidovudine and OLCICAN 450 MG each have the potential to cause neutropenia and anaemia. Some patients may not tolerate concomitant therapy at full dosage (see section 4.5). Didanosine plasma concentrations may increase during concomitant use with OLCICAN 450 MG, therefore patients should be closely monitored for didanosine toxicity (see section 4.5). Concomitant use of other medicines that are known to be myelosuppressive or associated with renal impairment with OLCICAN 450 MG may result in added toxicity (see section 4.5). Since OLCICAN 450 MG is considered a potential teratogen and carcinogen in humans, the tablets should be handled with caution. If a broken tablet makes direct contact with skin, the area should be washed thoroughly with soap and water.

The following medicines, valaciclovir, didanosine, nelfinavir, ciclosporin, omeprazole and mycophenolate mofetil did not affect the permeability of valganciclovir (rat in-situ model). OLCICAN 450 MG is metabolised to ganciclovir. Therefore, interactions associated with ganciclovir will be expected for OLCICAN 450 MG.

Interactions with ganciclovir

Imipenem-cilastatin

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. These medicines should not be used concomitantly.

Probenecid

Probenecid given with oral ganciclovir resulted in statistically significant 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 excretion. Therefore, patients taking probenecid and OLCICAN 450 MG should be closely monitored for ganciclovir toxicity.

Zidovudine

When zidovudine was given in the presence of oral ganciclovir there was a small (17 %), but statistically significant increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine, although this was not statistically significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, some patients may not tolerate concomitant therapy at full dosage (see section 4.4).

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both intravenous and oral). At ganciclovir oral doses of 3 and 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise 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. This increase cannot be explained by competition for renal tubular secretion, as there was an increase in the percentage of didanosine dose excreted. This increase could arise from either increased bioavailability or decreased metabolism. There was no clinically significant effect on ganciclovir concentrations. However, given the increase in didanosine plasma concentrations in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity (see section 4.4).

Mycophenolate Mofetil

Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment in which MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed, and patients monitored carefully.

Zalcitabine

Zalcitabine increased the AUC0-8h of oral ganciclovir by 13 %. There were no statistically significant changes in any of the other pharmacokinetic parameters assessed. Additionally, there were no clinically relevant changes in zalcitabine pharmacokinetics in the presence of oral ganciclovir although a small increase in the elimination rate constant was observed. Both OLCICAN 450 MG and zalcitabine have the potential to cause peripheral neuropathy and patients should be monitored for such events.

Stavudine

No statistically significant pharmacokinetic interactions were observed when stavudine and oral ganciclovir were given in combination.

Trimethoprim

Trimethoprim statistically significantly decreased the renal clearance of oral ganciclovir by 16,3 % and this was associated with a statistically significant decrease in the terminal elimination rate and the corresponding increase in half-life by 15 %. However, these changes are unlikely to be clinically significant, as AUC0-8h and Cmax were unaffected. The only statistically significant change in trimethoprim pharmacokinetic parameters when co-administered with ganciclovir was a 12 % increase in Cmin. However, this is unlikely to be of clinical significance and no dose adjustment is recommended.

Ciclosporin

There was no evidence that introduction of ganciclovir affects the pharmacokinetics of ciclosporin based on the comparison of ciclosporin trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.

Other potential interactions

Toxicity may be enhanced when ganciclovir is co-administered with, or is given immediately before or after, other medicines that inhibit replication of rapidly dividing cell populations such as occur in the bone marrow, tested and germinal layers of the skin and gastrointestinal mucosa, or that are associated with renal impairment (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfa combinations, nucleoside analogues and hydroxyurea). Therefore, these medicines should not be considered for concomitant use with OLCICAN 450 MG (see section 4.4).

Contraception in males and females

As a result of the potential for reproductive toxicity and teratogenicity, women of childbearing 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

Ganciclovir was shown to be teratogenic and embryotoxic. The safety of OLCICAN 450 MG in pregnant and lactating women has not been established.

Breastfeeding

Peri- and postnatal development has not been studied with OLCICAN 450 MG, but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the breast-fed infant cannot be discounted. Women using OLCICAN 450 MG should not breastfeed their infants.

Fertility

Based on clinical and nonclinical studies, it is considered likely that ganciclovir (and valganciclovir) may cause temporary or permanent inhibition of human spermatogenesis (see sections 4.4 and 5.3).

Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of valganciclovir as contained in OLCICAN 450 MG and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness including the patientu2019s ability to drive and operate machinery.

a. Tabulated summary of adverse reactions

b. Description of selected adverse reactions

Neutropenia

The risk of neutropenia is not predictable on the basis of the number of neutrophils before treatment. Neutropenia usually occurs during the first or second week of induction therapy. The cell count usually normalises within 2 to 5 days after discontinuation of the medicine or dose reduction (see section 4.4).

Thrombocytopenia

Severe thrombocytopenia may be associated with potentially life-threatening bleeding. Patients with low baseline platelet counts (< 100,000 /u03bcL) have an increased risk of developing thrombocytopenia. Patients with iatrogenic immunosuppression due to treatment with immunosuppressive drugs are at greater risk of thrombocytopenia than patients with AIDS (see section 4.4).

c. Post-marketing experience

Adverse events from post-marketing spontaneous reports with intravenous and oral ganciclovir not mentioned in any section above, and for which a causal relationship cannot be excluded are listed below. As OLCICAN 450 MG is rapidly and extensively converted to ganciclovir, such adverse events might also occur with OLCICAN 450 MG.

System Organ Class

Frequency

Undesirable effect

Immune system disorders

Frequency unknown

Anaphylactic reaction

d. 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 Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

It is expected that an overdose of OLCICAN 450 MG, could also possibly result in increased renal toxicity. Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of OLCICAN 450 MG.

Overdose experience with IV ganciclovir:

The majority of patients experienced one or more of the following adverse events:

• Haematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia.
• Hepatotoxicity: hepatitis, liver function disorder.
• Renal toxicity: worsening of haematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine.
• Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting.
• Neurotoxicity: generalised tremor, convulsion.