Cidofovir (cidofovir)

Cidofovir is commercially available as the dihydrate; dosage is expressed in terms of anhydrous drug.

Cidofovir is administered by slow IV infusion using a controlled-infusion device (e.g., pump).

Although cidofovir has been administered by intravitreal injection+, a preparation specifically for intravitreal administration is not commercially available in the US and the manufacturer states that direct intraocular injection of the currently available IV preparation of cidofovir (even if diluted) is contraindicated since such administration has been associated with iritis, ocular hypotony, and permanent visual impairment.

Cidofovir has been administered topically+ as a gel or cream for the management of certain mucocutaneous viral infections (e.g., acyclovir-resistant herpes simplex virus (HSV) infections). Although topical preparations of cidofovir are not commercially available in the US, a topical gel containing 1% cidofovir has been prepared extemporaneously using the IV preparation of cidofovir.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cidofovir/Selected Nephrotoxic Agents

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)

CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.

DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Antivirals/Talimogene Laherparepvec

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus (HSV-1) which has been modified to express human GM-CSF.(1)

CLINICAL EFFECTS: Administration of antiviral agents with activity against HSV-1 may interfere with the effectiveness of talimogene laherparepvec.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use when possible. Talimogene laherparepvec is a live, attenuated herpes simplex virus (HSV-1) which is injected into cancerous lesions where it replicates and produces GM-CSF, leading to lysis of tumors. It is sensitive to antiherpetic agents such as acyclovir, valacyclovir and famciclovir and so administration of these antivirals may impair talimogene laherparepvec effectiveness.(1)

DISCUSSION: Agents that inhibit herpes simplex virus activity may impair the ability of talimogene laherparepvec to replicate and produce GM-CSF in tumors. The impact of concurrent antiviral and talimogene laherparepvec therapy has not been studied; patients requiring antiviral prophylaxis or treatment with acyclovir, valacyclovir and famciclovir were excluded from clinical trials.(1) Agents linked to this monograph are systemic formulations of acyclovir, cidofovir, famciclovir, foscarnet, ganciclovir, valacyclovir and valganciclovir.

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Antivirals/Vusolimogene Oderparepvec

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vusolimogene oderparepvec is a genetically modified herpes simplex virus type 1 (HSV-1) oncolytic viral therapy.(1)

CLINICAL EFFECTS: Administration of antiviral agents with activity against HSV-1 may interfere with the effectiveness of vusolimogene oderparepvec.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving systemic antiviral treatment for herpetic infection should delay vusolimogene oderparepvec for 72 hours after completing antiviral therapy.(1)

DISCUSSION: Agents that inhibit herpes simplex virus activity may impair the ability of vusolimogene oderparepvec to replicate in tumors.(1) Antiviral agents with activity against HSV-1 include: acyclovir, cidofovir, famciclovir, foscarnet, ganciclovir, valacyclovir, and valganciclovir.

*Initiation in patients with serum creatinine >1.5 mg/dL, calculated creatinine clearance <=55 mL/minute, or urine protein concentration >=100 mg/dL (equivalent to >=2+ proteinuria).

*Concomitant use with other nephrotoxic drugs. Such agents must be discontinued at least 7 days prior to starting therapy with cidofovir injection.

*Hypersensitivity to cidofovir.

*History of clinically severe hypersensitivity to probenecid or other sulfa-containing drugs.

*Direct intraocular injection of the IV preparation.

• Renal disease with moderate to severe function impairment

• Neutropenic disorder

• Metabolic acidosis

Adverse effects reported in 15% or more of patients receiving cidofovir (with concomitant probenecid regimen) include nephrotoxicity (proteinuria, elevated serum creatinine), nausea and/or vomiting, fever, neutropenia, asthenia, headache, rash, infection, alopecia, diarrhea, pain, anemia, decreased IOP, anorexia, dyspnea, chills, increased cough, oral moniliasis, and decreased serum bicarbonate.

More Frequent

• Fever
• Nephrotoxicity
• Neutropenic disorder
• Proteinuria

Less Frequent

• Anemia
• Pneumonia

Rare or Very Rare

• Acute renal failure
• Iritis
• Metabolic acidosis
• Ocular hypotony
• Uveitis

More Frequent

• Alopecia
• Anorexia
• Diarrhea
• General weakness
• Headache disorder
• Nausea
• Skin rash
• Vomiting

Less Frequent

• Chills
• Cough
• Dyspnea
• Oral candidiasis

No enhanced messaging available.

Safety and efficacy of cidofovir have not been established in pediatric patients younger than 18 years of age.

Because of the risks of potential long-term carcinogenic and reproductive toxicity, cidofovir should be used with extreme caution in children+ with AIDS. The manufacturer states that the drug should be used in children only after careful evaluation and only when potential benefits outweigh risks.

Some experts state that cidofovir has not been studied in children with CMV disease, but can be considered for the management of CMV retinitis in HIV-infected children+ if other options cannot be used.

There are no adequate and well-controlled studies to date using cidofovir in pregnant women. Cidofovir should be used during pregnancy only if potential benefits justify risks to the fetus.

In animal studies, embryotoxicity (reduced fetal body weights) and maternal toxicity were observed in rats and rabbits receiving IV cidofovir at dosages of 1.5 and 1 mg/kg daily, respectively, during organogenesis. In rabbits receiving IV cidofovir in a dosage of 1 mg/kg daily, maternal toxicity and an increased incidence of fetal external, soft tissue, and skeletal anomalies (meningocele, short snout, and short maxillary bones) were observed.

Women of childbearing potential should be informed that cidofovir is embryotoxic in animals and should be advised to use an effective method of contraception during and for at least 1 month after cidofovir therapy.

Men should be advised to use a reliable method of barrier contraception during and for at least 3 months after cidofovir therapy.

It is not known whether cidofovir is distributed into human milk.

Since there is a potential for adverse effects in nursing infants and because carcinogenicity has been shown in animal studies, cidofovir should not be used in breast-feeding women.

Because of the risk of adverse effects in the infant and the risk of HIV transmission, the manufacturer states that HIV-infected women should not breast-feed infants.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

Dosage of cidofovir for geriatric patients should be selected with caution because of age-related decreases in renal function.

Safety and efficacy of cidofovir have not been evaluated in geriatric patients older than 60 years of age.

Because geriatric patients frequently have reduced glomerular filtration, particular attention should be paid to monitoring renal function prior to and during cidofovir therapy in this age group, and dosage should be modified in response to changes in renal function.