Di Du

Uses

Cytomegaloviral infections, Prophylaxis of cytomegaloviral infections in immunocompromised patients, Herpes simplex keratitis, CMV (cytomegalovirus) retinitis, Prophylaxis of cytomegaloviral infections in immunocompromised patients

Di Du is also used to associated treatment for these conditions: CMV colitis, Cytomegalovirus (CMV) Infection, Cytomegalovirus Retinitis, Cytomegalovirus gastroesophagitis, Varicella-zoster Progressive outer retinal necrosis, Acute Herpetic keratitis, Cytomegalovirus neurological disease, Varicella-zoster virus acute retinal necrosis

How Di Du works

Di Du's antiviral activity inhibits virus replication. This inhibitory action is highly selective as the drug must be converted to the active form by a virus-encoded cellular enzyme, thymidine kinase (TK). TK catalyzes phosphorylation of ganciclovir to the monophosphate, which is then subsequently converted into the diphosphate by cellular guanylate kinase and into the triphosphate by a number of cellular enzymes. In vitro, ganciclovir triphosphate stops replication of herpes viral DNA. When used as a substrate for viral DNA polymerase, ganciclovir triphosphate competitively inhibits dATP leading to the formation of 'faulty' DNA. This is where ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Di Du inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed.

Dosage

Di Du dosage

Ophthalmic-Herpes simplex keratitis:

• Adult: As 0.15% gel: Apply 1 drop in the inferior conjunctival sac of the affected eye 5 times daily (approx 3 hrly while awake) until corneal healing occurs, then 1 drop tid for 7 days after healing.

Intravenous-Cytomegaloviral infections:

• Adult: Induction: 5 mg/kg 12 hrly for 14-21 days. Maintenance: 5 mg/kg once daily for 7 days per wk or 6 mg/kg once daily for 5 days per wk. Doses to be given by IV infusion over 1 hr.

Intravenous-Prophylaxis of cytomegaloviral infections in immunocompromised patients:

• Adult: Induction: 5 mg/kg 12 hrly for 7-14 days. Maintenance: 5 mg/kg once daily for 7 days per wk or 6 mg/kg once daily for 5 days per wk. Doses to be given by IV infusion over 1 hr.

Side Effects

Most common adverse reactions reported in patients are blurred vision, eye irritation, punctate keratitis and conjunctival hyperemia.

Toxicity

Oral, mouse LD₅₀: > 2g/kg. Intravenous, dog LD₅₀: > 150mg/kg. Symptoms of overdose include irreversible pancytopenia, worsening GI symptoms, and acute renal failure. Suspected cancer agent.

Precaution

Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with Di Du. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the gel.

Interaction

Increased risk of haematologic toxicity with zidovudine. May increase serum levels of didanosine. Increased serum concentration with probenecid and other drugs that inhibit renal tubular secretion and resorption. Use of IV ganciclovir with oral mycophenolate mofetil may result in increased plasma concentrations of both drugs due to competition for renal tubular secretion. Concomitant use with immunosuppressive agents (e.g. azathioprine, ciclosporin, corticosteroids) may result in excessive suppression of bone marrow or the immune system. Generalised seizure may occur when taken with imipenem and cilastatin. Concurrent use with drugs that inhibit replication of rapidly dividing cells (e.g. dapsone, pentamidine, pyrimethamine, flucytosine, cytotoxic antineoplastic agents, amphotericin B, co-trimoxazole, other nucleoside analogues) may result in additive toxicity.

Food Interaction

• Take with food. Food increases bioavailability.

[Moderate] ADJUST DOSING INTERVAL: Food delays but enhances the oral absorption and bioavailability of ganciclovir capsules, possibly due to prolongation of gastrointestinal transit time.

In 20 HIV- and CMV-seropositive subjects, ganciclovir dosing (1000 mg every 8 hours) following a standardized high-fat breakfast increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ganciclovir by an average of 15% and 22%, respectively, compared to dosing after an overnight fast.

The time to reach peak plasma concentration (Tmax) was prolonged from 1.8 to 3 hours.

In another study of 15 such patients, administration of ganciclovir (2000 mg) within 30 minutes following a high-fat breakfast increased the Cmax and AUC an average of 111% and 114%, respectively, compared to administration in the fasting state (i.e. at least 1 hour before or 2 hours after a meal or snack).

Over the total day of dosing (2000 mg orally three times a day), there was a mean increase of 48% and 97% in Cmax and AUC, respectively, and a 36% decrease in half-life during administration with meals.

MANAGEMENT: To ensure maximal oral absorption, oral ganciclovir should be administered with or immediately after a meal.

Di Du Drug Interaction

Moderate: tacrolimus, tacrolimusMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprimUnknown: ciprofloxacin, ciprofloxacin, meperidine, meperidine, heparin, heparin, acetaminophen, acetaminophen, valproic acid, valproic acid, ondansetron, ondansetron

Di Du Disease Interaction

Major: bone marrow suppression, renal dysfunctionModerate: hemodialysis

Volume of Distribution

• 0.74 ± 0.15 L/kg

Elimination Route

Poorly absorbed systemically following oral administration. Bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9% (about 30% with a fatty meal).

Half Life

2.5 to 3.6 hours (mean 2.9 hours) when administered intravenously in adults. 3.1 to 5.5 hours when administered orally in adults. Renal function impairment causes a marked increase in half life (9 to 30 hours intravenously, 15.7 to 18.2 hours orally).

Clearance

• 128 +/- 63 mL/min [Patients with Renal Impairment (Clcr=50-79 mL/min)]
• 57+/- 8 mL/min [Patients with Renal Impairment (Clcr=25-49 mL/min)]
• 30 +/- 13 mL/min [Patients with Renal Impairment (Clcr<25 mL/min)]
• 4.7+/- 2.2 mL/min/kg [pediatric patients, aged 9 months to 12 years]

Elimination Route

Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir.

Pregnancy & Breastfeeding use

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Di Du should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: It is not known whether topical ophthalmic Di Du administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Caution should be exercised when Di Du is administered to nursing mothers.

Contraindication

Hypersensitivity to ganciclovir or valganciclovir and other antivirals (e.g. aciclovir, valaciclovir).

Special Warning

Use in children: Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Use in elderly patients: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Acute Overdose

Symptoms: Haematological toxicity (e.g. pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia); hepatotoxicity (e.g. hepatitis, liver function disorder); renal toxicity (e.g. worsening of haematuria in patient with renal impairment, acute renal failure, elevated creatinine); GI toxicity (e.g. abdominal pain, diarrhoea, vomiting); neurotoxicity (e.g. generalised tremor, convulsion).

Management: Symptomatic and supportive treatment. Haemodialysis and hydration may be useful in enhancing elimination of drug. For neutropenia, treatment with haematopoietic growth factors may be considered.

Storage Condition

Store between 20-25°C.

Innovators Monograph

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