Foscavir (foscarnet sodium)

Foscarnet is commercially available as the hydrated trisodium salt (i.e., foscarnet sodium); dosage is expressed in terms of foscarnet sodium.

Foscarnet sodium is administered by slow IV infusion using a controlled-infusion device (e.g., pump). The drug should not be administered by rapid IV infusion or direct IV injection since potentially toxic plasma foscarnet concentrations may result.

Foscarnet has been administered by intravitreal injection+; however, a preparation of the drug specifically for intravitreal administration is not commercially available in the US.

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.

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)

Selected Nephrotoxic Agents/Cidofovir

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)

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

Foscarnet/Selected Nephrotoxic Agents

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

MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)

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

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.

Foscarnet sodium is contraindicated in patients with clinically important hypersensitivity to the drug.

There are no contraindication contraindications for this drug.

• Dehydration
• Hyperphosphatemia
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Hypophosphatemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lower seizure threshold
• Seizure disorder

• Anemia
• Granulocytopenic disorder
• Neutropenic disorder

Adverse effects reported in 10% or more of patients receiving foscarnet include fever, nausea, anemia, diarrhea, abnormal renal function, vomiting, headache, seizures, and marrow suppression.

More Frequent

• Anemia
• Hypokalemia
• Hypomagnesemia
• Hypophosphatemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Nephrotoxicity

Less Frequent

• Abnormal ECG
• CNS toxicity
• Edema
• Granulocytopenic disorder
• Head sensation disturbance
• Hyperphosphatemia
• Hypertension
• Hypoproteinemia
• Hypotension
• Leukopenia
• Pancreatitis
• Seizure disorder
• Thrombocytopenic disorder
• Thrombotic disorder
• Urinary retention

Rare or Very Rare

• Acute renal failure
• Anaphylaxis
• Angioedema
• Aphthous stomatitis
• Cardiac arrest
• Diabetes insipidus
• Erythema multiforme
• Esophageal ulcer
• Extravasation injury
• Fanconi syndrome
• Gastrointestinal hemorrhage
• Glomerulonephritis
• Hematuria
• Hypersensitivity drug reaction
• Nephrotic syndrome
• Neutropenic disorder
• Pancytopenia
• Penile ulcerations
• Prolonged QT interval
• Renal tubular acidosis
• Renal tubular necrosis
• Rhabdomyolysis
• SIADH syndrome
• Stevens-johnson syndrome
• Torsades de pointes
• Toxic epidermal necrolysis
• Ulceration of vulva
• Ventricular arrhythmias

More Frequent

• Acute cognitive impairment
• Diarrhea
• Dizziness
• Fatigue
• Fever
• Gastrointestinal irritation
• Headache disorder
• Nausea
• Symptoms of anxiety
• Vomiting

Less Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Agitation
• Anorexia
• Arthralgia
• Ataxia
• Back pain
• Black tarry stools
• Chest pain
• Chills
• Constipation
• Cough
• Drowsy
• Dyschromia
• Dysgeusia
• Dysphagia
• Dyspnea
• Dysuria
• Facial edema
• Flushing
• General weakness
• Hyperhidrosis
• Injection site sequelae
• Insomnia
• Malaise
• Myalgia
• Nervousness
• Nocturia
• Ocular pain
• Pain
• Palpitations
• Polyuria
• Proteinuria
• Pruritus of skin
• Skin rash
• Tremor
• Xerostomia

Rare or Very Rare

• Circumoral edema
• Dehydration
• Depression
• Hypocalcemia
• Hypoesthesia
• Muscle weakness
• Myopathy
• Oral paresthesia
• Paresthesia
• Peripheral sensory neuropathy
• Urticaria
• Visual changes

No enhanced messaging available.

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

The manufacturer states that the drug should be used in children+only after careful evaluation and only when potential benefits of the drug outweigh possible risks.

Some experts recommend foscarnet as the preferred alternative for the management of CMV retinitis, acyclovir-resistant mucocutaneous HSV infections, and acyclovir-resistant varicella-zoster virus (VZV) infections in HIV-infected children+.

In animals, foscarnet is deposited in teeth and bone and such deposition is greater in those that are young and growing. Foscarnet adversely affects tooth enamel development in mice and rats; the effects of drug deposition on skeletal development have not been studied. There is evidence that foscarnet accumulates in bone in humans, but the extent to which this occurs has not been studied. Since foscarnet is deposited in human bone, it is likely that it does so to a greater degree in developing bone in children.

There are no adequate and well-controlled studies to date using foscarnet sodium in pregnant women. The drug should be used during pregnancy only when clearly needed.

Reproduction studies in female rats given subcutaneous foscarnet sodium in doses up to 75 mg/kg daily prior to and during mating, during gestation, and through 21 days postpartum caused a slight increase (less than 5%) in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation also caused an increased frequency of skeletal anomalies and variations. On the basis of estimated drug exposure (as measured by AUC), the 150- and 75-mg/kg doses were approximately one-eighth (rats) and one-third (rabbits) the estimated maximal daily human exposure. These data were inadequate to define the potential teratogenicity of foscarnet at dosages used in humans.

It is not known whether foscarnet is distributed into human milk. In lactating rats that received a dose of 75 mg/kg, the drug was distributed in maternal milk at concentrations 3 times higher than peak maternal blood concentrations.

Since there is potential for serious adverse reactions to foscarnet in nursing infants, a decision should be made to discontinue nursing or the drug, taking into consideration the importance of the drug to the woman.

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

Dosage of foscarnet sodium for geriatric patients should be selected with caution because of age-related decreases in renal function. (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Safety and efficacy of foscarnet have not been specifically studied in geriatric patients 65 years of age or older.

Adverse effects reported in patients 65 years of age or older have been similar to those reported in younger adults.

Because geriatric patients frequently have decreased renal function and because foscarnet is substantially excreted by the kidneys, particular attention should be paid to evaluating renal function prior to and during foscarnet therapy in this age group. If evidence of renal impairment exists or develops, appropriate dosage adjustments should be made. (See Renal Impairment under Dosage and Administration: Special Populations.)