GLOVIRAX

Indications

• Cytomegalovirus retinitis in immunocompromised patients
• Prevention of CMV disease in high-risk transplant recipients

Dosage

Children: For paediatric dosing, refer to the BNF for Children for specific guidance based on age, weight, and clinical condition.

Adults: The typical adult dosage for ganciclovir in the treatment of CMV retinitis is 5 mg/kg intravenously every 12 hours for 14 to 21 days, followed by maintenance therapy of 5 mg/kg once daily, adjusted based on renal function.

Mechanism of action

Ganciclovir's antiviral activity inhibits virus replication by being converted to its active form through phosphorylation by a virus-encoded enzyme, thymidine kinase. This active triphosphate form then competes with deoxyguanosine for incorporation into viral DNA, leading to the formation of faulty DNA and ultimately preventing DNA synthesis.

Pharmacodynamics

Ganciclovir is effective against human cytomegalovirus and other herpesviruses, including HSV-1, HSV-2, EBV, and VZV. It exhibits a higher affinity for viral DNA polymerases compared to cellular polymerases, allowing it to selectively inhibit viral replication while minimizing effects on host cell DNA synthesis.

Pharmacokinetics

Ganciclovir is administered intravenously and has a bioavailability of approximately 6-9% when given orally. It is widely distributed in the body, including the central nervous system, with a volume of distribution around 0.9 L/kg. The drug is primarily eliminated by the kidneys, and its half-life is approximately 2-4 hours in patients with normal renal function, with longer half-lives observed in those with renal impairment. Dose adjustments are recommended for patients with reduced renal function.

Contra-indications

• History of cytopenia
• Severe renal impairment (creatinine clearance less than or equal to 55 mL/min)
• Hypersensitivity to ganciclovir, aciclovir, valaciclovir, or famciclovir

Adverse effects

• Anaemia
• Leukopenia
• Neutropenia
• Thrombocytopenia
• Gastrointestinal discomfort
• Headache
• Insomnia
• Chills
• Confusion
• Nausea
• Fever
• Peripheral neuropathy
• Vision blurred
• Chest pain
• Arthralgia
• Asthenia
• Fatigue
• Malaise
• Muscle complaints
• Increased risk of infection
• Potential risk of ocular toxicity (iritis, hypotony, uveitis)

Interactions

• Leflunomide: unknown (increases exposure)
• Mycophenolate: unknown (increases risk of haematological toxicity)
• Nitisinone: unknown (increases exposure)
• Teriflunomide: unknown (increases exposure)

Precautions

• Caution in history of renal impairment
• Caution in hepatic impairment
• Regular eye examinations due to risk of ocular complications
• Women of childbearing potential should use effective contraception during and for at least 30 days after treatment
• Men with partners of childbearing potential should use barrier contraception during and for at least 90 days after treatment

Pregnancy

Manufacturer advises to avoid unless the potential benefit outweighs the risk, due to teratogenicity in animal studies.

Breast-feeding

Manufacturer advises to avoid due to potential presence of ganciclovir in breast milk and theoretical risk of bone marrow toxicity.

Storage

Store at room temperature in a dry place away from light.

Formulations

• Solution for infusion (Cidofovir 75 mg per 1 ml, Cidofovir 375 mg/5 ml concentrate for solution for infusion)

Mechanism of action

Ganciclovir'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. <i>In vitro</i>, 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. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed. Although the exact mechanism(s) of action of ganciclovir has not been fully elucidated, it appears that the drug exerts its antiviral effect on human cytomegalovirus and the other human herpesviruses by interfering with DNA synthesis via competition with deoxyguanosine for incorporation into viral DNA and by being incorporated into growing viral DNA chains. The active phosphorylated form of ganciclovir can both competitively inhibit viral DNA polymerase and be incorporated into growing DNA chains as a false nucleotide, thus interfering with chain elongation (prematurely terminating DNA synthesis) and/or resulting in formation of a mutant DNA chain and thereby inhibiting viral replication. Ganciclovir triphosphate apparently has no effect on viral protein or RNA synthesis. Cellular alpha-DNA polymerase also is inhibited by the drug, but generally at concentrations higher than those required for inhibition of viral DNA polymerase. In human bone marrow cells, the IC50 (concentration of drug that produces 50% inhibition of cell division) has been reported as 9.95 ug/ml. Unchanged ganciclovir does not appear to possess antiviral activity. Instead, the antiviral activity appears to depend principally on intracellular conversion of the drug to ganciclovir triphosphate. The formation of ganciclovir monophosphate appears to be the rate limiting step in the formation of ganciclovir triphosphate. In vitro in herpes viruses, ganciclovir triphosphate functions both as substrate for, and a preferential inhibitor of, viral DNA polymerase and as a false nucleotide base. In cells infected with herpes simplex virus type 1 or 2 or varicella-zoster virus, ganciclovir is converted to ganciclovir monophosphate via virus-coded thymidine kinase. The pathway for conversion to the monophosphate in cells infected with Epstein-Barr virus or cytomegalovirus is unclear; these viruses do not code for thymidine kinase, and a cellular deoxyguanosine kinase, found in the cytosol and in mitochondria, may be involved. In cytomegalovirus infected cells, increased concentrations of deoxyguanosine kinase (mitochondrial origin) have been detected, suggesting that the virus may induce production of the enzyme. Subsequent phosphorylation occurs via cellular kinases (including guanylate kinase, phosphoglycerate kinase, and nucleoside diphosphate kinase) to the diphosphate and then the active triphosphate form. Ganciclovir appears to be principally virustatic rather than virucidal in action. Following removal of the drug from the culture medium in vitro, viral DNA synthesis, which previously was inhibited, resumes, resulting in restored viral replication. In addition, clinical evidence of reactivated disease suggests that ganciclovir acts principally to suppress virus activity and that eradication of the virus does not appear to occur.

Pharmacodynamics

Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both <i>in vitro</i> and <i>in vivo</i>. Sensitive human viruses include cytomegalovirus (CMV), herpes simplex virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella zoster virus (VZV), however clinical studies have been limited to assessment of efficacy in patients with CMV infection. Ganciclovir is a prodrug that is structurally similar to acyclovir. It inhibits virus replication by its encorporation into viral DNA. This encorporation inhibits dATP and leads to defective DNA, ceasing or retarding the viral machinery required to spread the virus to other cells.