Foscarnet (Foscavir) is an antiviral medicine that is used primarily in the treatment of ganciclovir-resistant cytomegalovirus infection and Acyclovir-resistant herpes simplex and varicella zoster infections.

Foscarnet Uses:

• Treatment of Cytomegalovirus ophthalmic disease (retinitis):

  • Used in the treatment of cytomegalovirus (CMV) retinitis in persons with AIDS

• Herpes simplex virus:

  • Used in the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infection in immunocompromised persons (eg, with advanced AIDS)

• Off Label Use of Foscarnet in Adults:

  • Used in cytomegalovirus prevention in patients with allogeneic hematopoietic cell transplant recipients
  • Used in CMV treatment, gastrointestinal diseases such as esophagitis or colitis.
  • Used in the treatment of CMV neurological disease
  • Used in varicella-zoster virus infection of the eyes, progressive outer retinal necrosis

Foscarnet Dose in Adults

Foscarnet Dose in the treatment of Cytomegalovirus (CMV):

• Dose as an alternative agent in the treatment of Gastrointestinal disease (esophagitis, colitis) (off-label):
  • IV: 60 mg per kg per dose every 8 hours or 90 mg per kg per dose every 12 hours for 21 to 42 days or until symptom resolution.
• Dose in the treatment of Neurological disease (off-label):
  • IV: 60 mg per kg per dose every 8 hours or 90 mg per kg per dose every 12 hours in combination with ganciclovir; optimal duration not established.
• Dose in the treatment of Ophthalmic disease (retinitis):
  • IV (alternative agent):
    • Induction treatment:
      • 60 mg per kg per dose every 8 hours for 14 to 21 days or 90 mg per kg per dose every 12 hours for 14 to 21 days; for immediate sight-threatening lesions, administered in combination with intravitreal therapy.
    • Maintenance therapy:
      • 90 to 120 mg per kg per dose once in a day; due to lower toxicity, begin with 90 mg per kg per dose once in a day, may escalate to 120 mg per kg per dose once in a day if lower dose tolerated or for retinitis progression (manufacturer’s labeling).
      • Duration of maintenance therapy is ≥3 to 6 months and until lesions are inactive and until CD4 count is more than 100 cells per mm³ for 3 to 6 months in response to antiretroviral therapy in HIV-infected patients.
  • Intravitreal (off-label route):
    • Induction treatment:
      • 4 mg per 0.1 mL injected into vitreum (Diaz-Llopis 1994; HHS [OI adult 2019]) for 1 to 4 doses administered over 7 to 10 days for immediate sight-threatening lesions; must be used in combination with systemic antiviral therapy.

Foscarnet Dose as an alternative agent in the prevention of CMV infection in allogeneic hematopoietic cell transplant (HCT) recipients (off-label):

• Preemptive therapy: IV:

  • <100 days post-transplant:
    • Induction: 60 mg per kg per dose every 12 hours for 7 to 14 days, followed by
    • maintenance therapy: 90 mg per kg per dose once in a day if CMV is still detectable and declining, continue until indicator test is negative.
    • The minimum total duration (induction and maintenance) is 2 weeks.
  • >100 days post-transplant:
    • 60 mg per kg per dose every 12 hours for 14 days, continue treatment with 90 mg per kg per dose once in a day for 7 to 14 days until the indicator test is negative.

• Prophylactic therapy:

  • IV: 60 mg per kg per dose every 12 hours for 7 days, followed by 90 to 120 mg/kg/dose once a day until day 100 after HCT.

Foscarnet Dose in the treatment of Herpes simplex infection (acyclovir-resistant):

• Induction:

  • IV: 40 mg per kg per dose every 8 to 12 hours for 14 to 21 days.

Foscarnet Dose in the treatment of Varicella zoster virus (VZV) infection of the eyes, progressive outer retinal necrosis (PORN) (off-label):

• IV:
  • 90 mg per kg per dose every 12 hours (with or without IV ganciclovir) plus intravitreal antiviral therapy. Duration is based on virologic, clinical, and immunologic responses in consultation with an ophthalmologist.
• Intravitreal (off-label route):
  • 1.2 mg per 0.05 mL injected in the vitreum twice in a weak; must be used in combination with systemic antiviral therapy.

Foscarnet Dose in Children

Foscarnet Dose in the treatment of Cytomegalovirus (CMV) infection (HIV-exposed/-positive):

• Treatment induction:
  • In addition to antiviral therapy, antiretroviral therapy (ART) should be optimized.
• Dose in the treatment of CNS, neurological disease in children:
  • IV: 180 mg per kg per day in divided doses every 8 or 12 hours;
  • Use in combination with ganciclovir; begin treatment promptly and continue until symptom improvement; follow with chronic suppression
• Dose in the treatment of GI disease (esophagitis or colitis) in patients with ganciclovir-intolerant or ganciclovir-resistance:
  • IV: 180 mg per kg per day in divided doses every 8 or 12 hours for 21 to 42 days or until resolution of symptoms.
• Dose in the treatment of Retinitis: Use as a component of initial therapy if immediate, sight-threatening lesions are present.
  • Infants and Children: 
    • IV: 180 mg per kg per day in divided doses every 8 or 12 hours;
    • Continue the treatment for 14 to 21 days.
    • Use in combination with ganciclovir if monotherapy fails or in sight-threatening illnesses. Follow treatment with chronic suppression.
  • Adolescents:
    • Combination therapy with intravitreal and intravenous antiviral therapy recommended; follow treatment/induction with chronic suppression.
    • IV: 180 mg per kg per day in divided doses every 8 or 12 hours for 14 to 21 days
    • Intravitreal: 2.4 mg per dose for 1 to 4 doses administered over 7 to 10 days in combination with valganciclovir (oral), foscarnet (IV), ganciclovir (IV),  or cidofovir (IV)
• Dose in the maintenance therapy of Chronic suppressive:
  • Secondary prophylaxis (following treatment for prior disseminated disease, retinitis, or neurologic disease or GI disease with relapse):
  • Infants, Children, and Adolescents:
    • IV: 90 to 120 mg per kg per dose once in a day;
    • The duration of therapy dependent on multiple factors (eg, age, CD4 cell count, infection, and response) and is typically several months.
• Dose as an alternate agent in the treatment of Cytomegalovirus (CMV) infection after stem cell transplantation (HSCT) in children:

  • Preemptive therapy:

    • Induction:
      • less than 100 days post-transplant:
        • Induction: 60 mg per kg per dose every 12 hours for 7 to 14 days; follow with maintenance therapy if CMV is still detectable and declining
      • >100 days post-transplant:
        • 60 mg per kg per dose every 12 hours for 14 days; follow with maintenance therapy
    • Maintenance:
      • 90 mg per kg per dose once in a day; duration dependent on post-transplant days:
      • less than 100 days post-transplant:
        • Minimum duration is at least in a weak and continue daily until CMV indicator test is negative
      • more than 100 days post-transplant:
        • Continue for 7 to 14 days or until CMV indicator test is negative

  • Prophylactic therapy:

    • Engraftment to <100 days post-transplant:
      • 60 mg per kg per dose every 12 hours for a weak, followed by 90 to 120 mg per kg per dose once daily until day 100 after HSCT

Foscarnet Dose in the treatment of acyclovir-resistant Herpes simplex virus (HSV) infection; (HIV-exposed/positive):

• Infants and Children:

  • IV: 120 mg per kg per day in divided doses every 8 or 12 hours;
  • The duration of treatment depends on the site of the infection.

• Adolescents:

  • IV: 80 to 120 mg per kg per day in divided doses every 8 or 12 hours;
  • continue until clinical response.

Foscarnet Dose in the treatment of Varicella zoster virus (VZ) infection (HIV-exposed/-positive):

• Treatment of Chickenpox not responding to acyclovir:

  • Infants and Children:
    • IV: 120 to 180 mg per kg per day in divided doses every 8 hours for 7 to 10 days or until no new lesions have appeared for 48 hours.

• Treatment of Zoster: Progressive outer retinal necrosis:

  • Infants, Children, and Adolescents:
  • Note: In addition to antiviral therapy, optimize ART.
    • IV:
      • 90 mg per kg per dose every 12 hours in combination with ganciclovir (systemic, IV) and intravitreal foscarnet and/or ganciclovir
    • Intravitreal:
      • 1.2 mg per 0.05 mL per dose two times in a weak  in combination with systemic foscarnet and ganciclovir and/or intravitreal ganciclovir

Foscarnet Pregnancy Category: C

• Limited information is available on the use of pregnancy.
• To detect oligohydramnios, it is recommended to monitor the amniotic fluid volume by ultrasound every 20 weeks.

Foscarnet use during breastfeeding:

• Foscarnet may be present in breast milk, but it is unknown.
• To reduce the risk of HIV transmission, pregnant women with HIV should stop breastfeeding.
• The manufacturer is concerned about the possibility of serious adverse reactions in breastfeeding infants and recommends that a decision be made regarding whether to discontinue breastfeeding or discontinue using the drug.
• This consideration will also take into account the importance to the mother.

Foscarnit Dose in Kidney disease:

Note: Renal function may be estimated by dividing actual 24-hour CrCl (mL/minute) by body weight (kg) or by using the modified Cockcroft-Gault formula ([140 − age]/[serum creatinine in mg/dL × 72] [× 0.85 for females]) for dosage adjustment purposes.

Induction Dosing of Foscarnet in Patients With Abnormal Renal Function

Maintenance Dosing of Foscarnet in Patients With Abnormal Renal Function

• Hemodialysis:

  • Foscarnet is highly removed by hemodialysis (up to ~38 percent in 2.5 hours HD with high-flux membrane).
  • Doses of 45 to 60 mg per kg per dose post hemodialysis (thrice in a weak) with the monitoring of weekly plasma concentrations to maintain peak plasma concentrations in the range of 500 to 800 micromolar for the treatment of CMV infection have been recommended.

• Peritoneal dialysis:

  • HSV infection (localized or disseminated): IV:
    • 60 mg per kg per dose every 48 to 72 hours;
    • higher doses may be necessary for herpes encephalitis or herpes zoster infection.

Dose in Liver disease:

The manufacturer’s labeling hasn't provided any dosage adjustments.

Common Side Effects of Foscarnet:

• Central Nervous System:

  • Headache

• Endocrine & Metabolic:

  • Hypocalcemia
  • Hypomagnesemia
  • Hypokalemia
  • Hypophosphatemia

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Vomiting

• Hematologic & Oncologic:

  • Anemia
  • Granulocytopenia

• Renal:

  • Renal Insufficiency

• Miscellaneous:

  • Fever

Less Common Side Effects Of Foscarnet:

• Cardiovascular:

  • First Degree Atrioventricular Block
  • Flushing
  • Hypertension
  • Hypotension
  • Chest Pain
  • Edema
  • Facial Edema
  • Palpitations
  • Sinus Tachycardia
  • ST Segment Changes On ECG
  • Thrombosis

• Central Nervous System:

  • Dizziness
  • Fatigue
  • Hypoesthesia
  • Malaise
  • Neuropathy
  • Pain
  • Paresthesia
  • Seizure
  • Anxiety
  • Confusion
  • Depression
  • Rigors
  • Abnormal Electroencephalogram
  • Aggressive Behavior
  • Agitation
  • Amnesia
  • Aphasia
  • Ataxia
  • Cerebrovascular Disease
  • Dementia
  • Hallucination
  • Insomnia
  • Meningitis
  • Nervousness
  • Sensory Disturbance
  • Somnolence
  • Stupor

• Dermatologic:

  • Erythematous Rash
  • Maculopapular Rash
  • Pruritus
  • Seborrhea
  • Diaphoresis
  • Skin Rash
  • Dermal Ulcer
  • Skin Discoloration

• Endocrine & Metabolic:

  • Electrolyte Disturbance
  • Abnormal Albumin-Globulin Ratio
  • Acidosis
  • Albuminuria
  • Cachexia
  • Hyponatremia
  • Hyperphosphatemia
  • Increased Lactate Dehydrogenase
  • Increased Thirst
  • Weight Loss

• Gastrointestinal:

  • Aphthous Stomatitis
  • Cachexia
  • Constipation
  • Dysgeusia
  • Dyspepsia
  • Dysphagia
  • Flatulence
  • Melena
  • Abdominal Pain
  • Anorexia
  • Pancreatitis
  • Xerostomia

• Genitourinary:

  • Nephrotoxicity
  • Dysuria
  • Nocturia
  • Urinary Retention
  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Mineral Abnormalities
  • Neutropenia
  • Abnormal White Cell Differential
  • Altered Platelet Function
  • Lymphadenopathy
  • Pseudolymphoma
  • Bone Marrow Suppression
  • Leukopenia
  • Rectal Hemorrhage
  • Sarcoma
  • Thrombocytopenia

• Hepatic:

  • Abnormal Hepatic Function Tests
  • Increased Lactate Dehydrogenase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum ALT
  • Increased Serum AST

• Infection:

  • Infection
  • Sepsis
  • Abscess
  • Bacterial Infection
  • Fungal Infection

• Local:

  • Inflammation At Injection Site
  • Pain At Injection Site

• Neuromuscular & Skeletal:

  • Weakness
  • Arthralgia
  • Back Pain
  • Leg Cramps
  • Myalgia
  • Muscle Spasm
  • Neuropathy
  • Tremor

• Ophthalmic:

  • Visual Disturbance
  • Conjunctivitis
  • Eye Pain

• Renal:

  • Increased Serum Creatinine
  • Acute Renal Failure
  • Increased Blood Urea Nitrogen
  • Decreased Creatinine Clearanc
  • Polyuria

• Respiratory:

  • Hemoptysis
  • Pharyngitis
  • Pneumonia
  • Pneumothorax
  • Pulmonary Infiltrates
  • Respiratory Failure
  • Respiratory Insufficiency
  • Rhinitis
  • Sinusitis
  • Cough
  • Dyspnea
  • Bronchospasm
  • Flu-Like Symptoms
  • Stridor

Contraindications to Foscarnet:

Clinically significant hypersensitivity to foscarnet and any component of this formulation.

Warnings and precautions

• Dental effects:

  • Foscarnet can be found in the teeth and bones of young animals. It has negatively affected the development of tooth enamel in rats.

• Electrolyte imbalance:

  • Imbalance of serum electrolytes or minerals occurs in at least 15 percent of patients (hyper/hypophosphatemia, hypocalcemia, low ionized calcium, hypomagnesemia, or hypokalemia); reducing infusion rate may decrease or prevent the symptoms.
  • Low ionized calcium patients may experience perioral discomfort, paresthesias and tetany.
  • Before initiating therapy, ensure that your electrolytes are correct.
  • Patients with electrolyte imbalances or neurologic problems, as well as those taking calcium-dependent medications, should be cautious.
  • Patients with electrolyte imbalance symptoms or signs should seek immediate medical attention.
  • Be careful when you are taking any medications that can cause electrolyte imbalances.

• Hematologic effects

  • It can cause anemia or granulocytopenia.

• Hypersensitivity

  • There have been reports of severe hypersensitivity reactions including angioedema or anaphylactic shock.
  • If you experience an acute reaction, stop immediately and seek medical treatment.

• Renal impairment: [US-Boxed Warning]

  • Foscarnet can cause some renal impairment in a majority of patients.;
  • It is possible to develop renal impairment at any time, though it usually occurs during the second week induction therapy.
  • However, many patients have died from renal failure in less than 4 weeks after stopping foscarnet. Therefore, both maintenance and induction therapy should be closely monitored for renal function.
  • For renal dysfunction, dosage adjustments are recommended.
  • Safety and efficacy are not guaranteed for patients with serum creatinine levels greater than 2.8 mg/dL or CrCl lower than 50 mL/minute.
  • To avoid overdosing, calculate CrCl before treatment begins.
  • It is not recommended for patients with CrCl below 0.4 mL/kg per minute.
  • A good hydration can reduce the risk of nephrotoxicity.

• Extension of QT

  • Reports of QT prolongation have been made, including torsades es.
  • Some reports were also reported in patients with confounding risks factors, such as electrolyte abnormalities, concomitant medication, or underlying cardiac disease.
  • Patients with a history or increased risk of QT prolongation should be cautious.

• Seizures: [US Boxed Warning]:

  • Possible seizures due to mineral imbalance and plasma electrolyte may occur
  • The incidence of HIV has been reported in as high as 10% of HIV-positive patients.
  • Low total serum calcium, impaired baseline renal function and an underlying CNS condition are all risk factors for seizures.
  • Patients who have had seizures in the past have sometimes been able stop or start again after receiving foscarnet treatment.
  • This is usually after their electrolyte or mineral abnormality has been corrected or their underlying condition treated.

• Vascular irritant:

  • To avoid tissue irritation and ulceration, only administer into a vein that has adequate blood flow.
  • There have been reports of genital vascular tissue injury; it is important to hydrate properly.

• Heart failure:

  • Patients with heart disease should be cautious when using this product due to its sodium content.

Foscarnet: Drug Interaction

Monitoring parameters:

• 24-hour creatinine clearance,
• ECG, and electrolytes at baseline and periodically thereafter (when clinically appropriate).

During induction therapy:

• Obtain complete blood counts, and electrolytes (including calcium, magnesium, potassium, serum creatinine, and phosphorus) twice a week and then 7 days during maintenance therapy.
• More frequent monitoring may be required in some patients. Check hydration status before and after infusion.

How to administer Foscarnet?

IV:

• Foscarnet is administered by intravenous infusion, using an infusion pump, at a rate not exceeding 1 mg per kg per minute.
• Adult induction doses of 60 mg per kg are administered over 1 hour.
• Adult maintenance doses of 90 to 120 mg per kg are infused over 2 hours.
• Undiluted (24 mg per mL) solution can be administered without further dilution when using a central venous catheter for infusion.
• For peripheral vein administration, the solution must be diluted to a final concentration not to exceed 12 mg per mL.
• The manufacturer recommends 750 to 1,000 mL of NS or D5W be administered prior to the first infusion to establish diuresis.
• With subsequent infusions of 90 to 120 mg per kg, this volume would be repeated.
• If the dose were 40 to 60 mg per kg, then the volume could be reduced to 500 mL.
• After the first dose, the hydration fluid should be administered concurrently with foscarnet.

Intravitreal: Off-label route:

• Withdraw solution directly from infusion bottle as it is already diluted to the appropriate concentration for intravitreal administration. Pass through 0.22-micron filter prior to injection.

Mechanism of action of Foscarnet:

• A pyrophosphate analog acts as a noncompetitive inhibitor of many viral DNA polymerases and viral RNA. 
• Foscarnet, which is similar to ganciclovir and a virostatic drug, can be used. Foscarnet doesn't require activation via thymidinekinase.

Protein binding:

• 14 percent to 17 percent

Metabolism:

• Biotransformation does not occur.

Half-life elimination:

• Elimination: ~3 to 4 hours;
• Terminal: ~88 hours (due to bone deposition)

Excretion:

• Urine (≤28 percent  as unchanged drug)

International Brand Names of Foscarnet:

• Foscarnet Elea
• Foscarnet Filaxis
• Foscarnet Richmond
• Foscavir
• Fu Shi Ling
• Terap
• Foscavir
• Carnet
• Triapten

Foscarnet Brand Names in Pakistan:

There is no brand available in Pakistan.