Formulary Kit

INDICATIONS AND CLINICAL USE:

IVOZFO™ (fosfomycin for injection) is indicated for the treatment of the following infections in adults and children including neonates:

• Bacterial meningitis
• Bone and joint infections
• Complicated intra-abdominal infections
• Complicated skin and soft tissue infections
• Complicated urinary tract infections
• Hospital-acquired pneumonia, including ventilator-associated pneumonia
• Infective endocarditis 
• Bacteremia that occurs in association with, or is suspected to be associated with, any of the infections listed above

IVOZFO should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of the infections listed above, or when these alternative antibacterial agents have failed to demonstrate efficacy. Fosfomycin should usually be used as part of a combination antibacterial regimen. Relevant clinical treatment guidelines can be referred to for identifying the most appropriate combination partner to use with fosfomycin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of IVOZFO and other antibacterial drugs, IVOZFO should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of IVOZFO in pediatric patients has been established; therefore, Health Canada has authorized an indication for pediatric use.

Pediatrics (<12 years of age and <40 kg body weight): Consult the specific Pediatric dosing guidelines in the Product Monograph. Safety and efficacy of fosfomycin in neonates and children with renal impairment have not been evaluated in clinical trials.

Adolescents (12–17 years of age and >40 kg body weight): The recommended doses for adults should be used in adolescent patients (12–17 years of age).

Geriatrics (>65 years of age): There was no difference in drug efficacy or tolerance for patients older than 65 years compared with patients younger than 65 years. Caution is advised when considering the use of doses at the higher end of the recommended range.

SERIOUS WARNINGS AND PRECAUTIONS:

OTHER RELEVANT WARNINGS AND PRECAUTIONS:

General

Limitations of the clinical data

It is recommended that fosfomycin is selected to treat the listed indications only when it is considered inappropriate to use antibacterial agents that are commonly recommended for their initial treatment.

The clinical data to support the use of intravenous fosfomycin for treatment of some of the listed indications is limited by a lack of adequate randomized controlled trials. Furthermore, various dose regimens have been used and no single intravenous dose regimen has been strongly supported by clinical trial data.

Cardiovascular

Risk of sodium overload

1 g IVOZFO (fosfomycin for injection) (equivalent to 1.32 g fosfomycin sodium) contains 14 mmol (320 mg) sodium, equivalent to 16% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

Due to the additional sodium load, the risk of hypernatremia and fluid overload should be assessed before starting treatment. Caution is advised when IVOZFO is used in patients with a history of congestive heart failure or underlying comorbidities such as nephrotic syndrome, liver cirrhosis, hypertension, hyperaldosteronism, hypernatremia, pulmonary edema, or hypoalbuminemia as well as in neonates under sodium restriction. A low-sodium diet is recommended during treatment.

A high sodium load may also result in decreased levels of potassium in serum or plasma (i.e., hypokalemia), which may require supplementation. Hypokalemia may result in varied symptoms such as weakness, tiredness, or edema and/or muscle twitching. Severe forms may cause hyporeflexia and cardiac arrhythmia. Hypernatremia may be associated with hypertension and signs of fluid overload such as edema.

The action of cardiac glycosides can be potentiated by potassium deficiency.

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including IVOZFO. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against C. difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile. Surgical evaluation should be instituted as clinically indicated as surgical intervention may be required in certain severe cases.

Haematological Reactions (including agranulocytosis)

In patients receiving fosfomycin intravenously haematological reactions including neutropenia or agranulocytosis have occurred. Therefore, the leukocyte count should be monitored at regular intervals and if such reactions occur, an adequate medical treatment should be initiated.

Hepatic/Biliary/Pancreatic

Liver injury, usually reversible upon discontinuation of therapy, has been seen with use of fosfomycin, including hepatitis. There is no requirement for dosage adjustments in patients with hepatic insufficiency since the pharmacokinetics of fosfomycin remains unaffected in this patient group.

Patients with hepatic cirrhosis should be closely monitored for sodium overload.

Immune

Acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur in very rare cases. At the first signs (including sweating, nausea, cyanosis), the infusion of IVOZFO must be immediately discontinued.

Monitoring and Laboratory Tests

One vial with 2 g of IVOZFO contains 28 mmol (640 mg) sodium, one vial with 4 g IVOZFO contains 56 mmol (1,280 mg) sodium and one vial with 8 g of IVOZFO contains 111 mmol (2,560 mg) sodium.

A high sodium load associated with the use of IVOZFO may result in decreased levels of potassium in serum or plasma. Serum electrolytes (particularly sodium, potassium, and phosphate) and water balance must be monitored regularly during therapy, in particular when using the high-dose regimens (>16 g/day in adults; >300 mg/kg/day in children), and for all doses in neonates and premature infants due to variable renal sodium excretion.

Renal

In patients with impaired renal function, the dosage should be adjusted according to the grade of renal insufficiency. Consult the Dosage in renal insufficiency section in the Product Monograph. Data on fosfomycin clearance by continuous veno-venous hemofiltration is very limited and fosfomycin clearance may be extensive. Patients undergoing renal replacement therapy should be closely monitored for clinical efficacy and for adverse events.

Fosfomycin is primarily excreted unchanged by the kidneys. In patients with severe renal insufficiency (creatinine clearance ≤40 mL/min), the elimination of IVOZFO is substantially slowed.

Reproductive Health

Fertility

To date, in humans no reduction in fertility after therapy with fosfomycin has been reported. In male and female rats, reduced fertility was observed after the oral administration of fosfomycin at supra-therapeutic doses.

Sensitivity/Resistance

Development of Drug-Resistant Bacteria and Need for Combination Therapy

Prescribing IVOZFO in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

In vitro, fosfomycin has been found to rapidly select for resistant mutants. Also, the use of intravenous fosfomycin alone has been associated with selection of resistance in clinical studies. Whenever possible, it is recommended that fosfomycin is administered as part of a combination antibacterial drug regimen to reduce the risk of selecting for resistance.

FOR MORE INFORMATION:

For important information relating to adverse reactions, special populations, drug interactions, and dosing information which have not been discussed in this piece, please consult the Product Monograph at www.veritypharma.com/products/

The Product Monograph is also available by calling us at 1-800-977-9778.

Reference: Verity Pharmaceuticals, Inc. IVOZFO Product Monograph. May 28, 2024.