Vistide

Cidofovir is an antiviral medication that prevents certain viral cells from multiplying in your body.

Cidofovir is used to treat an eye infection called cytomegalovirus retinitis (CMV) in people who have AIDS (acquired immunodeficiency syndrome). Cidofovir is not a cure for CMV or AIDS.

Cidofovir is for treating CMV only in people who have AIDS.

Cidofovir may also be used for purposes not listed in this medication guide.

Cidofovir is for treating cytomegalovirus retinitis (CMV) only in people who have AIDS (acquired immunodeficiency syndrome).

You should not receive cidofovir if you have moderate to severe kidney disease, or a history of severe allergic reaction to probenecid (Benemid) or sulfa drugs.

Cidofovir can harm your kidneys. You should not receive cidofovir if you have used any of the following drugs within the past 7 days: antivirals, chemotherapy, injected antibiotics, medicine for bowel disorders, medicine to prevent organ transplant rejection, injectable medications to treat osteoporosis or Paget's disease, and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).

Cidofovir can harm your kidneys after only one or two doses. You will be given other medications to help keep your kidneys working properly while you are receiving cidofovir.

Your kidney function will be tested before you receive each dose of cidofovir. You may need frequent blood tests to be sure this medication is not causing other harmful effects. Your AIDS treatments may be delayed based on the results of these tests.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

You should not receive cidofovir if you are allergic to it, or if you have:

• moderate to severe kidney disease; or
• a history of severe allergic reaction to probenecid (Benemid) or sulfa drugs.

Cidofovir can harm your kidneys. This effect is increased when you also use certain other medicines. Your doctor may need to change your treatment plan if you have used any of the following drugs within the past 7 days:

• medicines to treat a bowel disorder;
• medication to prevent organ transplant rejection;
• antiviral medications;
• injectable medications to treat osteoporosis or Paget's disease of bone;
• chemotherapy;
• some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve); or
• any injected antibiotics.

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

• mild kidney disease;
• diabetes; or
• pancreas or liver problems.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

FDA pregnancy category C. It is not known whether cidofovir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Use an effective form of birth control while you are using cidofovir and for at least 1 month after your treatment ends.

This medication can affect fertility (ability to have children) in men. If a man fathers a child while using this medication, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 3 months after you stop using cidofovir.

It is not known whether cidofovir passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Patients should be advised that VISTIDE is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during and following treatment. Patients receiving VISTIDE should be advised to have regular follow-up ophthalmologic examinations. Patients may also experience other manifestations of CMV disease despite VISTIDE therapy.

HIV-infected patients may continue taking antiretroviral therapy, but those taking zidovudine should be advised to temporarily discontinue zidovudine administration or decrease their zidovudine dose by 50%, on days of VISTIDE administration only, because probenecid reduces metabolic clearance of zidovudine.

Patients should be informed of the major toxicity of VISTIDE, namely renal impairment, and that dose modification, including reduction, interruption, and possibly discontinuation, may be required. Close monitoring of renal function (routine urinalysis and serum creatinine) while on therapy should be emphasized.

The importance of completing a full course of probenecid with each VISTIDE dose should be emphasized. Patients should be warned of potential adverse events caused by probenecid (e.g., headache, nausea, vomiting, and hypersensitivity reactions). Hypersensitivity/allergic reactions may include rash, fever, chills and anaphylaxis. Administration of probenecid after a meal or use of antiemetics may decrease the nausea. Prophylactic or therapeutic antihistamines and/or acetaminophen can be used to ameliorate hypersensitivity reactions.

Patients should be advised that cidofovir causes tumors, primarily mammary adenocarcinomas, in rats. VISTIDE should be considered a potential carcinogen in humans (See Carcinogenesis, Mutagenesis, & Impairment Of Fertility). Women should be advised of the limited enrollment of women in clinical trials of VISTIDE.

Patients should be advised that VISTIDE caused reduced testes weight and hypospermia in animals. Such changes may occur in humans and cause infertility. Women of childbearing potential should be advised that cidofovir is embryotoxic in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during and for 1 month following treatment with VISTIDE. Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with VISTIDE.

Cidofovir is an antiviral medication that works by preventing certain viral cells from multiplying in your body.

Cidofovir is used to treat an eye infection called cytomegalovirus retinitis (CMV) in people who are infected with HIV (human immunodeficiency virus).

Cidofovir may also be used for purposes other than those listed in this medication guide.

Vistide is a prescription medication used to treat cytomegaloviral (CMV) retinitis, which is a viral inflammation of the eye, in people with acquired immune deficiency syndrome (AIDS).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite, which has in vitro and in vivo antiviral activity.1 2 3 5 7 11 12 13 15 16 18 24

• Cidofovir diphosphate interferes with viral DNA synthesis and inhibits viral replication10 11 12 13 25 by competitive inhibition of viral DNA polymerase6 14 16 and incorporation and termination of the growing viral DNA chain.1 3 The inhibitory activity of cidofovir diphosphate is highly selective1 9 10 11 12 20 because of its greater affinity for viral DNA polymerases5 than for human DNA polymerases.1 3

• Active against various Herpesviridae, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV).1 3 16 24 33 Also active in vitro against adenovirus,3 16 24 human papillomavirus (HPV),3 24 33 and human polyomavirus.1 2 3 7 11 13 15 16 18 24 30 34

• Has in vitro activity against poxviruses, including vaccinia virus (cowpox), monkeypox, and variola virus (the causative agent of smallpox).45 46 47 53 57 65 67 68 Also has in vivo activity against monkeypox in animal models53 65 66 67 68 and against vaccinia virus in mice.47 48 53 54 55 56

• May be active against some ganciclovir-resistant CMV2 9 27 and some acyclovir-resistant HSV.2 18

• CMV resistant to cidofovir can be selected in vitro.1

It is very important that your doctor check you at regular visits for any blood problems that may be caused by this medicine.

It is very important that your ophthalmologist (eye doctor) check your eyes at regular visits since it is still possible that you may have some loss of eyesight during cidofovir treatment.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Medicines like cidofovir can sometimes cause serious side effects such as blood problems and kidney problems; these are described below. Cidofovir has also been found to cause cancer in animals, and there is a chance it could cause cancer in humans as well. Discuss these possible side effects with your doctor.

Check with your doctor immediately if any of the following side effects occur:

• Fever, chills, or sore throat

Check with your doctor as soon as possible if any of the following side effects occur:

• Decreased urination
• increased thirst and urination

• Decreased vision or any change in vision

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• headache
• loss of appetite
• nausea
• vomiting

• Generalized weakness
• loss of strength

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you need to store Vistide at home, talk with your doctor, nurse, or pharmacist about how to store it.

Vistide® is the brand name for cidofovir injection. The chemical name of cidofovir is 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C8H14N3O6P•2H2O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:

Cidofovir is a white crystalline powder with an aqueous solubility of ≥ 170 mg/mL at pH 6–8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.

Vistide is a sterile, hypertonic aqueous solution for intravenous infusion only. The solution is clear and colorless. It is supplied in clear glass vials, each containing 375 mg of anhydrous cidofovir in 5 mL aqueous solution at a concentration of 75 mg/mL. The formulation is pH-adjusted to 7.4 with sodium hydroxide and/or hydrochloric acid and contains no preservatives. The appropriate volume of Vistide must be removed from the single-use vial and diluted prior to administration (see DOSAGE AND ADMINISTRATION).

Vistide MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.

Dosage

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. Vistide MUST BE DILUTED IN 100 MILLILITERS 0.9% (NORMAL) SALINE PRIOR TO ADMINISTRATION. TO MINIMIZE POTENTIAL NEPHROTOXICITY, PROBENECID AND INTRAVENOUS SALINE PREHYDRATION MUST BE ADMINISTERED WITH EACH Vistide INFUSION.

Induction Treatment

The recommended induction dose of Vistide for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks. Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of Vistide. CrCl (mL/min) should be calculated according to the following formula:

Maintenance Treatment

The recommended maintenance dose of Vistide is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr), administered once every 2 weeks.

Dose Adjustment

The maintenance dose of Vistide must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 – 0.4 mg/dL above baseline. Vistide therapy must be discontinued for an increase in serum creatinine of ≥ 0.5 mg/dL above baseline or development of ≥ 3+ proteinuria.

Vistide is contraindicated in patients with a serum creatinine concentration > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).

Probenecid

Probenecid must be administered orally with each Vistide dose. Two grams must be administered 3 hr prior to the Vistide dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr Vistide infusion (for a total of 4 grams).

Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting. Administration of an antiemetic may reduce the potential for nausea associated with probenecid ingestion. In patients who develop allergic or hypersensitivity symptoms to probenecid, the use of an appropriate prophylactic or therapeutic antihistamine and/or acetaminophen should be considered (see CONTRAINDICATIONS).

Hydration

Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of Vistide. The saline solution should be infused over a 1–2 hr period immediately before the Vistide infusion. Patients who can tolerate the additional fluid load should receive a second liter. If administered, the second liter of saline should be initiated either at the start of the Vistide infusion or immediately afterwards, and infused over a 1 to 3 hr period.

Method of Preparation and Administration

Inspect vials visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vial should not be used. With a syringe, extract the appropriate volume of Vistide from the vial and transfer the dose to an infusion bag containing 100 mL 0.9% (normal) saline solution. Infuse the entire volume intravenously into the patient at a constant rate over a 1 hr period. Use of a standard infusion pump for administration is recommended.

It is recommended that Vistide infusion admixtures be administered within 24 hr of preparation and that refrigerator or freezer storage not be used to extend this 24 hr limit.

If admixtures are not intended for immediate use, they may be stored under refrigeration (2–8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.

The chemical stability of Vistide admixtures was demonstrated in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles. No data are available to support the addition of other drugs or supplements to the cidofovir admixture for concurrent administration.

Vistide is supplied in single-use vials. Partially used vials should be discarded (see Handling and Disposal).

Compatibility with Ringer's solution, Lactated Ringer's solution or bacteriostatic infusion fluids has not been evaluated.

Handling and Disposal

Due to the mutagenic properties of cidofovir, adequate precautions including the use of appropriate safety equipment are recommended for the preparation, administration, and disposal of Vistide. The National Institutes of Health presently recommends that such agents be prepared in a Class II laminar flow biological safety cabinet and that personnel preparing drugs of this class wear surgical gloves and a closed front surgical-type gown with knit cuffs. If Vistide contacts the skin, wash membranes and flush thoroughly with water. Excess Vistide and all other materials used in the admixture preparation and administration should be placed in a leak-proof, puncture-proof container. The recommended method of disposal is high temperature incineration.

Patient Monitoring

Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose. In patients with proteinuria, intravenous hydration should be administered and the test repeated. Intraocular pressure, visual acuity and ocular symptoms should be monitored periodically.

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September 2010

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