Foscavir

This medication is given by injection into a vein by a health care professional in a hospital or clinic setting. If you are using this medication at home, learn all preparation and usage instruction from your health care professional. If you have any questions about using this medication properly, consult your doctor or pharmacist.Before using this product, check it visually for particles or discoloration. If either is present, do not use the liquid. It is usually infused slowly over 1 to 2 hours using an infusion pump. Infusing this medication too quickly can result in serious side effects. Do not mix with any other medications. When starting this medication, you will receive 2 to 3 doses per day for the first 2 to 3 weeks of treatment. This starting period is called "induction." Once induction is completed, you will then be given this medication usually once a day for the remainder of treatment. Dosage is based on your weight, kidney function, medical condition, and response to treatment.To prevent kidney damage, it is important to drink plenty of fluids while using this medication. Fluids may be given by vein to make sure you get enough.Antivirals work best when the amount of medicine in your body is kept at a constant level. Therefore, use this drug at evenly spaced intervals.It is very important to continue using this medication exactly as prescribed by your doctor. Stopping treatment too soon may result in ineffective treatment.Do not use more of this drug or infuse it more often or faster than prescribed by your doctor. Your condition will not improve faster, and you may experience side effects.If skin contact occurs, flush with plenty of water. If irritation occurs, contact your doctor immediately.Learn how to store and discard needles, medical supplies, and any unused medication safely. Consult your pharmacist. Never reuse needles or syringes.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may harm the kidneys (e.g., amphotericin B, cidofovir, aminoglycosides such as amikacin/gentamicin/tobramycin), pentamidine, "water pills" (diuretics), zidovudine.This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Foscarnet is injected into a vein through an IV using an infusion pump. The medicine enters the body through a catheter placed into the vein. A healthcare provider will show you how to use an infusion pump. Do not self-inject foscarnet if you do not understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You may also be given IV fluids to keep you from getting dehydrated.

You may need to mix foscarnet with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine. Do not give foscarnet with other medicines in the same IV line.

Foscarnet should be clear and colorless. Do not use the medicine if it has changed colors or has any particles in it. Call your doctor for a new prescription.

The medicine must be injected slowly and can take up to 2 hours to complete. Injecting foscarnet too fast can cause dangerous or unwanted side effects.

Foscarnet is usually given for 2 to 3 weeks. Follow your doctor's dosing instructions very carefully.

While using foscarnet, your kidney function and electrolytes (potassium, sodium, magnesium, phosphorus) will need to be tested often, and you may also need regular eye exams.

Store foscarnet at room temperature away from very hot or very cold temperature.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

Call your doctor for instructions if you miss a dose of foscarnet.

• Astrazeneca

• Clinigen Healthcare Ltd.

WARNING

RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF FOSCARNET SODIUM INJECTION. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF FOSCARNET SODIUM INJECTION, IS IMPERATIVE.

SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH FOSCARNET SODIUM INJECTION TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED.

FOSCARNET SODIUM INJECTION IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR-RESISTANT HSV INFECTIONS.

THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see WARNINGS). Approximately 33% of 189 patients with AIDS and CMV retinitis who received FOSCAVIR (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥ 2.0 mg/dL). The incidence of renal impairment in subsequent clinical trials in which 1000 mL of normal saline or 5% dextrose solution was given with each infusion of FOSCAVIR was 12% (34/280).

FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia (15–30%), hypophosphatemia (8–26%) and hyperphosphatemia (6%), hypomagnesemia (15– 30%), and hypokalemia (16–48%) (see WARNINGS). The higher percentages were derived from those patients receiving hydration.

FOSCAVIR treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies (see WARNINGS). Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions predisposing the patient to seizures. The rate of seizures did not increase with duration of treatment. Three cases were associated with overdoses of FOSCAVIR (see OVERDOSE).

In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 9. These figures were calculated without reference to drug relationship or severity.

TABLE 9
Adverse Events Reported in Five Controlled US Clinical Trials

	n = 189		n = 189
Fever	65%	Abnormal Renal Function	27%
Nausea	47%	Vomiting	26%
Anemia	33%	Headache	26%
Diarrhea	30%	Seizures	10%

From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 10. Although death was specifically attributed to FOSCAVIR in only one case, other complications of FOSCAVIR (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths (see WARNINGS).

TABLE 10
Severe Adverse Events

	n = 189
Death	14%
Abnormal Renal Function	14%
Marrow Suppression	10%
Anemia	9%
Seizures	7%

From the five initial U.S. controlled trials of FOSCAVIR, the following list of adverse events has been compiled regardless of causal relationship to FOSCAVIR. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications.

Incidence Of 5% Or Greater

Body as a Whole: fever, fatigue, rigors, asthenia, malaise, pain, infection, sepsis, death

Central and Peripheral Nervous System: headache, paresthesia, dizziness, involuntary muscle contractions, hypoesthesia, neuropathy, seizures including grand mal seizures (see WARNINGS)

Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain

Hematologic: anemia, granulocytopenia, leukopenia, neutropenia (see PRECAUTIONS)

Metabolic and Nutritional: mineral and electrolyte imbalances (see WARNINGS) including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia

Psychiatric: depression, confusion, anxiety

Respiratory System: coughing, dyspnea

Skin and Appendages: rash, increased sweating

Urinary: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function (see WARNINGS)

Special Senses: vision abnormalities

Incidence Between 1% And 5%

Application Site: injection site pain, injection site inflammation

Body as a Whole: back pain, chest pain (including reports of transient chest pain as part of infusion reactions), edema, influenza-like symptoms, bacterial infections, moniliasis, fungal infections, abscess

Cardiovascular: hypertension, palpitations, ECG abnormalities including sinus tachycardia, first degree AV block and non-specific ST-T segment changes, hypotension, flushing, cerebrovascular disorder (see WARNINGS)

Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities (see WARNINGS)

Gastrointestinal: constipation, dysphagia, dyspepsia, rectal hemorrhage, dry mouth, melena, flatulence, ulcerative stomatitis, pancreatitis

Hematologic: thrombocytopenia, platelet abnormalities, thrombosis, white blood cell abnormalities, lymphadenopathy

Liver and Biliary: abnormal A-G ratio, abnormal hepatic function, increased SGPT, increased SGOT

Metabolic and Nutritional: hyponatremia, decreased weight, increased alkaline phosphatase, increased LDH, increased BUN, acidosis, cachexia, thirst

Musculo-Skeletal:arthralgia, myalgia

Neoplasms: lymphoma-like disorder, sarcoma

Psychiatric: insomnia, somnolence, nervousness, amnesia, agitation, aggressive reaction, hallucination

Respiratory System: pneumonia, sinusitis, pharyngitis, rhinitis, respiratory disorders, respiratory insufficiency, pulmonary infiltration, stridor, pneumothorax, hemoptysis, bronchospasm Skin and

Appendages: pruritus, skin ulceration, seborrhea, erythematous rash, maculopapular rash, skin discoloration

Special Senses: taste perversions, eye abnormalities, eye pain, conjunctivitis

Urinary System:albuminuria, dysuria, polyuria, urethral disorder, urinary retention, urinary tract infections, acute renal failure, nocturia, facial edema

Selected adverse events occurring at a rate of less than 1% in the five initial U.S. controlled clinical trials of FOSCAVIR include: syndrome of inappropriate antidiuretic hormone secretion, pancytopenia, hematuria, dehydration, hypoproteinemia, increases in amylase and creatinine phosphokinase, cardiac arrest, coma, and other cardiovascular and neurologic complications.

Selected adverse event data from the Foscarnet vs. Ganciclovir CMV Retinitis Trial (FGCRT), performed by the Studies of the Ocular Complications of AIDS (SOCA) Research Group, are shown in Table 11 (see Clinical Trials).

TABLE 11
FGRCT: Selected Adverse Events*

EVENT	GANCICLOVIR			FOSCARNET
	No. of Events	No.of Patients	Rates†	No. of Events	No.of Patients	Rates†
Absolute neutrophil count decreasing to <0.50 x 109 per liter	63	41	1.30	31	17	0.72
Serum creatinine increasing to >260 µmol per liter (>2.9 mg/dL)	6	4	0.12	13	9	0.30
Seizure ‡	21	13	0.37	19	13	0.37
Catheterization-related infection	49	27	1.26	51	28	1.46
Hospitalization	209	91	4.74	202	75	5.03
* Values for the treatment groups refer only to patients who completed at least one follow-up visit – i.e., 133 to 119 patientsin the ganciclovir group and 93 to 100 in the foscarnet group. “Events” denotes all events observed and “patients” the numberof patients with one or more of the indicated events. †Per person-year at risk ‡Final frozen SOCA I database dated October 1991

Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with FOSCAVIR or ganciclovir monotherapy are shown in Table 12. The most common reason for a treatment change in patients assigned to either FOSCAVIR or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity.

TABLE 12
CRRT: Selected Adverse Events

 

	Foscavir N=88			Ganciclovir N=93			Combination N=93
	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†
Anemia (Hgb <70g/L)	11	7	0.20	9	7	0.14	19	15	0.33
Neutropenia‡
ANC <0.75 x 109 cells/L	86	32	1.53	95	41	1.51	107	51	1.91
ANC <0.50 x 109 cells/L	50	25	0.91	49	28	0.80	50	28	0.85
Thrombocytopenia
Platelets <50 x 109/L	28	14	0.50	19	8	0.43	40	15	0.56
Platelets <20 x 109/L	1	1	0.01	6	2	0.05	7	6	0.18
Nephrotoxicity
Creatinine >260 μmol/L (>2.9 mg/dL)	9	7	0.15	10	7	0.17	11	10	0.20
Seizures	6	6	0.17	7	6	0.15	10	5	0.18
Hospitalizations	86	53	1.86	111	59	2.36	118	64	2.36
* Pts. = patients with event; †Rate = events/person/year; ‡ANC = absolute neutrophil count

Adverse events that have been reported in post-marketing surveillance include: administration site extravasation, localized edema, hypersensitivity reactions (including anaphylactic shock, urticaria and angioedema) (see WARNINGS), gastrointestinal hemorrhage, increased lipase, glomerulonephritis, nephrotic syndrome, proteinuria, status epilepticus, ventricular arrhythmia, prolongation of QT interval, torsade de pointes (see WARNINGS), gamma GT increased, diabetes insipidus (usually nephrogenic), renal calculus, Fanconi syndrome acquired, renal tubular acidosis, renal tubular necrosis, crystal-induced nephropathy, hypercalcemia, hypernatremia, esophageal ulceration and muscle disorders including myopathy, myositis, muscle weakness and rare cases of rhabdomyolysis. Cases of vesiculobullous eruptions including erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported. In most cases, patients were taking other medications that have been associated with toxic epidermal necrolysis or Stevens-Johnson syndrome.

Read the entire FDA prescribing information for Foscavir (Foscarnet Sodium Injection)

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You should not use foscarnet if you are allergic to it.

To make sure foscarnet is safe for you, tell your doctor if you have:

• kidney disease;

• heart disease, heart rhythm disorder;

• personal or family history of long QT syndrome;

• an electrolyte imbalance (such as low levels of calcium, potassium, or magnesium in your blood);

• epilepsy or other seizure disorder; or

• if you are on a low salt diet.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether foscarnet passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Foscarnet can harm your kidneys. This effect is increased when you also use certain other medicines, including: antivirals, chemotherapy, injected antibiotics, medicine for bowel disorders, medicine to prevent organ transplant rejection, injectable osteoporosis medication, and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).

Tell your doctor about all your current medicines and any you start or stop using, especially:

• anagrelide, cilostazol, donepezil, fluconazole, methadone, ondansetron;

• an antibiotic or antifungal medicine--azithromycin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, levofloxacin, moxifloxacin, pentamidine, telithromycin;

• cancer medicine--arsenic trioxide, oxaliplatin, vandetanib;

• an antidepressant--citalopram, escitalopram;

• anti-malaria medication--chloroquine, halofantrine;

• heart rhythm medicine--amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, procainamide, quinidine, sotalol; or

• medicine to treat a psychiatric disorder--chlorpromazine, droperidol, haloperidol, pimozide, thioridazine.

This list is not complete. Other drugs may interact with foscarnet, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Cytomegalovirus (CMV) Infection

Treatment of CMV retinitis in HIV-infected patients.1 2 3 4 33 Foscarnet is not curative; stabilization or improvement of ocular manifestations may occur, but progression of retinitis is possible during or following treatment.1 2 3 4

Drugs of choice for initial induction and maintenance therapy of CMV retinitis are IV ganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen.33 62 A regimen of both ganciclovir and foscarnet is used for treatment of CMV retinitis in patients who have relapsed following monotherapy with either drug.1 63 64

Long-term suppressive or maintenance therapy (secondary prophylaxis) of recurrent CMV disease† in HIV-infected adults, adolescents, or children†.38 USPHS/IDSA recommends IV ganciclovir or IV foscarnet as drugs of choice for such prophylaxis.38

Prophylaxis or preemptive treatment of CMV disease in adult and pediatric allogeneic or autologous hematopoietic stem cell transplant (HSCT) recipients†.39 CDC, IDSA, and ASBMT recommend IV foscarnet as an alternative to IV ganciclovir in HSCT recipients, especially when ganciclovir cannot be tolerated or when ganciclovir-resistant CMV may be involved.39

Safety and efficacy not established for treatment of extraocular CMV infections or for CMV infections in immunocompetent individuals.1

Mucocutaneous Herpes Simplex Virus (HSV) Infections

Treatment of acyclovir-resistant mucocutaneous HSV (HSV-1 and HSV-2) infections (e.g., orofacial, genital, digital) in immunocompromised patients (e.g., those with AIDS).1 33 40 41 42 43 44 45 46 48 49 50 51 56 57 73

Safety and efficacy not established for treatment of other HSV infections, such as retinitis, encephalitis, and congenital neonatal HSV disease, or for HSV infections in immunocompetent individuals.1

Chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence of HSV infections† in HIV-infected individuals who have frequent or severe recurrences.59

Drugs of choice for secondary prophylaxis are oral acyclovir or oral famciclovir in adults and adolescents and oral acyclovir in infants and children; IV foscarnet and IV cidofovir are alternatives for such prophylaxis if acyclovir-resistant HSV is suspected.59

Varicella-Zoster Infections

Management of acyclovir-resistant varicella-zoster infections† in patients with AIDS.50 52 53 70

Specific Drugs

Drug	Interaction	Comments
Aminoglycosides	Possible increased nephrotoxicity1	Avoid concomitant use unless potential benefits outweigh risks1
Amphotericin B	Possible increased nephrotoxicity1	Avoid concomitant use unless potential benefits outweigh risks1
Drugs affecting calcium	Possible additive effects on serum calcium concentrations; foscarnet decreases calcium1	Use concomitantly with particular caution1
Ganciclovir	No apparent effect on ganciclovir or foscarnet pharmacokinetics with concomitant or alternating therapy with the drugs.1 In vitro evidence of synergistic antiviral activity.1
Pentamidine	Possible hypocalcemia when used with IV pentamidine;1 not reported to date with aerosolized pentamidine1	Avoid concomitant use unless potential benefits outweigh risks1
Ritonavir	Possible abnormal renal function when used with ritonavir (with or without saquinavir)1

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Foscavir, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Foscavir. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Foscavir.

Review Date: October 4, 2017

Foscavir is the brand name for foscarnet sodium. The chemical name of foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration with an empirical formula of Na3CO5P•6 H2O and a molecular weight of 300.1. The structural formula is:

Foscavir has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. Foscavir INJECTION is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of Foscavir contains 24 mg of foscarnet sodium hexahydrate in Water for Injection, USP. Hydrochloric acid may have been added to adjust the pH of the solution to 7.4. Foscavir INJECTION contains no preservatives.