Cidofovir and Cytomegaloviral Retinitis - Defeating the Silent Threat

Overview:

Cidofovir is an antiviral medication used to treat certain viral infections caused by DNA viruses. It works by inhibiting the replication of viral DNA within infected cells. Cidofovir is primarily used for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS, a viral infection that affects the eyes and can cause vision loss. It is available as an injectable formulation and is administered under medical supervision. The United States Food and Drug Administration approved Cidofovir for CMV retinitis in June 1996. It is important to note that Cidofovir may have potential side effects and should be used only as directed by a healthcare professional.

For Patients:

What Is Cytomegaloviral Retinitis?

Cytomegaloviral retinitis is a viral infection that affects the retina, the tissue in the back of the eye that is light-sensitive. It is caused by the cytomegalovirus (CMV), which is a member of the herpesvirus family. CMV retinitis most commonly occurs in individuals with a weakened immune system, particularly those with advanced HIV or AIDS.

In people with a healthy immune system, the immune response keeps the CMV infection under control. However, in individuals with a compromised immune system, such as those with AIDS, the virus can multiply and cause damage to the retina. CMV retinitis can lead to vision loss if left untreated or if it worsens despite medical intervention.

Symptoms of CMV retinitis may include blurry vision, floaters (spots or cobwebs in the visual field), decreased peripheral vision, and, in severe cases, complete vision loss. If any of these symptoms occur, it is important to seek medical attention promptly.

How Is Cidofovir Given?

Starting (Induction) Treatment for Cidofovir:

• The recommended dose of Cidofovir for patients with normal kidney function is 5 mg per kg of body weight.

• It is administered once weekly for two consecutive weeks.

Maintenance Treatment for Cidofovir:

• After completing the induction treatment, the recommended maintenance dose for patients with normal kidney function is 5 mg per kg of body weight.

• It is administered once every two weeks.

Dose Adjustment for Cidofovir:

• Individuals with kidney problems may not be suitable candidates for Cidofovir treatment.

• Kidney function will be assessed through urine or blood tests before each Cidofovir infusion.

• If there is evidence of decreased kidney function, the Cidofovir dose may be interrupted or discontinued, depending on the individual case.

How Effective is Cidofovir?

Researchers compared high-dose intravenous Cidofovir to standard-dose intravenous ganciclovir (another antiviral medication commonly used for CMV retinitis). They found that both treatments were similarly effective in delaying disease progression and preserving visual acuity in patients with AIDS-related CMV retinitis.

What Are the Things to Inform the Doctor Before Taking Cidofovir?

Avoid using Cidofovir if one has:

• Allergy to Cidofovir or any of its ingredients.

• History of kidney disease.

• Serious allergy to Probenecid or other sulfa-containing medicines, making it impossible to take Probenecid.

Warnings and Precautions:

• Kidney damage is a significant risk associated with Cidofovir. Close monitoring is necessary, especially in patients with existing kidney problems or undergoing hemodialysis.

• Use caution in the case of diabetes mellitus, as Cidofovir may increase the risk of ocular hypotony (low eye pressure).

• Regular eye examinations are recommended during Cidofovir treatment to detect eye irritation, inflammation, or swelling. Notify the doctor promptly in case of eye pain, redness, itching, or changes in vision.

• Cidofovir has been shown to cause reduced testes weight and low sperm count in animals. While not observed in human studies, similar effects may occur, leading to infertility. Men should use barrier birth control methods during Cidofovir treatment and for three months thereafter.

• Cidofovir is not indicated for the treatment of HIV infection. It does not prevent HIV transmission, so precautions to avoid infecting others should be continued.

• Cidofovir has not been studied in children and should not be administered to pediatric patients.

• Inform the doctor about all medications being taken, including over-the-counter drugs, as they may interact with Cidofovir or Probenecid.

What Are the Side Effects of Cidofovir?

The side effects of Cidofovir include:

Very common side effects:

• Low white blood cell counts.

• Headache.

• Nausea.

• Vomiting.

• Protein in the urine.

• Increase in blood creatinine (a measure of kidney function).

• Hair loss.

• Rash.

• Weakness or fatigue.

• Fever.

Common side effects:

• Inflammation of the eye.

• Reduced pressure in the eyes.

• Difficult or labored breathing.

• Shortness of breath.

• Diarrhea.

• Chills.

Any pain, redness, itching of the eye, or changes in vision should be promptly reported to the doctor for review.

How to Use Cidofovir?

• Cidofovir is administered through an intravenous infusion (drip into a vein).

• It should not be administered through other methods, such as intraocular injection or topical application on the skin.

• Cidofovir should only be given by a doctor or nurse with experience treating AIDS.

• The appropriate dose of Cidofovir is transferred from the vial to a 100 ml infusion bag containing normal saline solution (0.9 percent).

• The entire volume of the infusion bag is administered into the vein at a constant rate over one hour using a standard infusion pump.

• It is important not to exceed the recommended dose, frequency of use, or rate of infusion.

What Should Be Done if a Dose Is Missed?

If a dose of Cidofovir is missed, it is important to follow the instructions provided by a healthcare professional or the prescribing information.

What Should Be Done to Treat Cidofovir Overdose?

In the event of a Cidofovir overdose, immediate medical attention should be sought. The specific treatment for an overdose may vary depending on the symptoms and severity. Prompt medical intervention is crucial to manage any potential complications and provide appropriate supportive care.

How to Store Cidofovir?

• Ensure that this medication is stored in a place where children cannot see or reach it.

• Do not use this medication after the expiration date indicated on the label.

• Store this medication below 77° Fahrenheit and avoid refrigerating or freezing it.

• Avoid disposing of any unused medicines through wastewater or household waste. Consult the pharmacist for guidance on how to dispose of medications there no longer need properly. Following these measures will contribute to protecting the environment.

For Doctors:

Indication:

Cidofovir is indicated for the treatment of cytomegalovirus retinitis.

Dosage:

• Induction Therapy: Administer 5 mg/kg (milligrams per kilogram) of the medication intravenously (IV) through a one-hour infusion once a week for two weeks. Prior to and following each infusion, provide saline hydration and administer Probenecid.

• Maintenance Therapy: Administer 5 mg/kg of the medication intravenously (IV) through a one-hour infusion every other week. Prior to and following each infusion, provide saline hydration and administer Probenecid. Continue therapy for a period of three to six months, or until the lesions are inactive and the CD4+ count remains above 100 cells/mcL for three to six months in response to antiretroviral therapy (ART) therapy.

Dosing Considerations:

• Patients with preexisting renal impairment are advised against using this medication if they have a serum creatinine level greater than 1.5 mg/dL, a calculated creatinine clearance (CrCl) of 55 mL/min or lower, or a urine protein level of 100 mg/dL or higher (equivalent to 2+ proteinuria or above).

• In cases where renal impairment develops during therapy, the maintenance dose should be reduced to 3 mg/kg if there is an increase in serum creatinine of 0.3 to 0.4 mg/dL above the baseline level. However, if there is an increase of 0.5 mg/dL or more above the baseline or the development of 3+ or higher proteinuria, the therapy should be discontinued.

Pharmacology:

Mechanism of Action:

Cidofovir selectively inhibits viral DNA polymerase, a key enzyme involved in the replication of the virus. Biochemical studies have shown that Cidofovir diphosphate, the active form of Cidofovir within cells, specifically inhibits the DNA polymerase of cytomegalovirus (CMV). Notably, the concentrations required to inhibit herpesvirus polymerases with Cidofovir diphosphate are significantly lower (8- to 600-fold) than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. By incorporating Cidofovir into the growing viral DNA chain, the rate of viral DNA synthesis is reduced.

Pharmacodynamics:

Cidofovir is a recently developed antiviral medication, that belongs to the class of nucleotide analogs. It exhibits activity against retinitis infections caused by cytomegalovirus (CMV), a common viral infection that affects the majority of adults. By selectively inhibiting the synthesis of viral DNA, Cidofovir effectively suppresses CMV replication.

Pharmacokinetics:

Absorption:

• Cidofovir reaches its maximum plasma concentration immediately after the infusion.

Distribution:

• Only a small fraction of Cidofovir, approximately 0.5 percent, is bound to proteins in the plasma.

• The apparent volume of distribution of Cidofovir ranges from 410 to 537 mL/kg, indicating extensive distribution throughout the body.

Metabolism:

• Cidofovir undergoes extensive metabolism within the cells.

• Cidofovir diphosphate, the intracellular active metabolite of Cidofovir, plays a crucial role in its antiviral activity. Cidofovir monophosphate, another metabolite of Cidofovir, is inactive and does not contribute to its therapeutic activity.

Excretion:

• The primary route of excretion for Cidofovir is through the kidneys, accounting for approximately 70 to 100 percent of the drug eliminated from the body.

• The renal clearance rate of Cidofovir is approximately 130 mL/kg/hr, indicating efficient elimination through the kidneys.

• The total body clearance of Cidofovir is approximately 150 mL/kg/hr, reflecting the combined effect of renal and non-renal elimination pathways.

Elimination Half-Life:

• Cidofovir (Adult): In adults, the elimination half-life of Cidofovir is around 2.5 hours, indicating a relatively short duration of time for the drug to be cleared from the body.

• Cidofovir (Pediatric): In pediatric patients, the elimination half-life of Cidofovir is longer, averaging around 9.5 hours.

• Cidofovir Diphosphate: The active metabolite, Cidofovir diphosphate, has a significantly longer elimination half-life of approximately 17 hours, indicating a prolonged duration of action.

Toxicity:

Long-term studies assessing the carcinogenic potential of Cidofovir have not been conducted. However, Cidofovir demonstrated mutagenic activity in some in vitro tests, indicating the potential to cause genetic mutations. The impact of Cidofovir on fertility in humans has not been extensively studied. Animal studies have shown adverse effects on fertility, including reduced fertility and reproductive organ abnormalities. It is important to discuss potential risks and benefits with a healthcare professional before using Cidofovir, especially in individuals of reproductive age or those planning to have children.

Contraindications:

• Avoid administering nephrotoxic substances in the seven days following the initiation of Cidofovir treatment.

• Refrain from directly injecting Cidofovir into the eye.

• Do not administer Cidofovir to patients who have shown hypersensitivity to Cidofovir, severe hypersensitivity to Probenecid, or sulfa-containing medications in the past.

• Exercise caution when prescribing Cidofovir to patients with a serum creatinine level higher than 1.5 mg/dL, a calculated creatinine clearance (CrCl) of 55 mL/min or less, or a urine protein level of 100 mg/dL or higher (equivalent to 2+ proteinuria).

Warnings and Precautions:

Endocrine and Metabolic:

• There have been reported cases of metabolic acidosis linked to liver dysfunction and pancreatitis, which in some instances have resulted in fatalities.

• Reports have shown decreased serum bicarbonate associated with proximal tubal injury and renal wasting syndrome.

Ocular:

• Reports indicate decreased intraocular pressure, occasionally accompanied by decreased visual acuity. Regular monitoring is advised.

• Instances of uveitis and iritis have been reported. Regular monitoring is recommended.

Drug Interactions:

The drug interactions of Cidofovir are as listed:

• Amikacin.

• Dibekacin.

• Foscarnet.

• Framycetin.

• Gentamicin.

• Kanamycin.

• Neomycin.

• Netilmicin.

• Pentamidine.

• Streptomycin.

• Tobramycin.

Other Specifications:

Cidofovir in Pregnant Women:

• Cidofovir should not be administered to pregnant individuals, as it has been shown to cause harm to unborn animals. Consult the doctor immediately if the patient becomes pregnant while receiving Cidofovir.

• Women of childbearing potential should use effective contraception during Cidofovir treatment and for six months after completing treatment.

• Men receiving Cidofovir should use effective contraception and avoid fathering a child during treatment and for three months after completing treatment.

Cidofovir in Lactating Women:

• Cidofovir should not be used by individuals who are breastfeeding. It is uncertain whether Cidofovir is transferred to infants through breast milk. Nursing mothers should discontinue Cidofovir or stop breastfeeding if they continue to receive Cidofovir.

• Women with HIV should avoid breastfeeding to prevent transmitting HIV to their infants through breast milk.

Cidofovir in Pediatrics:

Cidofovir use in pediatric patients should be approached with caution and under the guidance of a healthcare professional. The safety and efficacy of Cidofovir in this population are not fully established, and proper monitoring is essential.

Cidofovir in Geriatrics:

Cidofovir use in geriatric patients should be closely monitored and adjusted based on individual factors such as renal function and comorbidities.