Vistide Side Effects

Generic Name: cidofovir

Please note - some side effects for Vistide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Vistide - for the Consumer

Vistide

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Vistide:

Decreased appetite; diarrhea; hair loss; headache; nausea; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Vistide:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody of black, tarry stools; chest pain; chills; confusion; dark urine; decreased urination; depression; eye inflammation or irritation; fast heartbeat; fever; hallucinations; loss of coordination; numbness or tingling of the skin, hands, or feet; seizures; severe or persistent sore throat or cough; shortness of breath; stomach pain; sudden weight gain; swelling or bloating; tremors; unsteady movements; unusual bruising or bleeding; unusual tiredness or weakness; vision changes; white patches in the mouth; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Vistide Side Effects - for the Professional

Vistide

1.

Nephrotoxicity: Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creatinine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving Vistide at a maintenance dose of 5 mg/kg every other week. Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107). Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely.

2.

Neutropenia: In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.

3.

Decreased Intraocular Pressure/Ocular Hypotony: Among the subset of patients monitored for intraocular pressure changes, a ≥ 50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose. Severe hypotony (intraocular pressure of 0–1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.

4.

Anterior Uveitis/Iritis: Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving Vistide therapy. Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing. Treatment with topical corticosteroids with or without topical cycloplegic agents may be considered. Patients should be monitored for signs and symptoms of uveitis/iritis during Vistide therapy.

5.

Metabolic Acidosis: A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to ≤ 16 mEq/L occurred in 16% of cidofovir-treated patients. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Vistide.

In clinical trials, Vistide was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.

The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.

Table 4. Serious Clinical Adverse Events or Laboratory Abnormalities Occurring in > 5% of Patients

	N = 135* # patients (%)
* Patients receiving 5 mg/kg maintenance regimen in Studies 105, 106 and 107. † Defined as decreased intraocular pressure (IOP) to ≤ 50% that at baseline. Based on 70 patients receiving 5 mg/kg maintenance dosing (Studies 105, 106 and 107), for whom baseline and follow-up IOP determinations were recorded.
Proteinuria (≥ 100 mg/dL)	68	(50)
Neutropenia (≤ 500 cells/mm3)	33	(24)
Decreased Intraocular Pressure†	17	(24)
Decreased Serum Bicarbonate (≤ 16 mEq/L)	21	(16)
Fever	19	(14)
Infection	16	(12)
Creatinine Elevation (≥ 2.0 mg/dL)	16	(12)
Pneumonia	12	(9)
Dyspnea	11	(8)
Nausea with Vomiting	10	(7)

The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.

The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of Vistide and are listed below regardless of causal relationship to Vistide. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.

Body as a Whole: abdominal pain, accidental injury, AIDS, allergic reaction, back pain, catheter blocked, cellulitis, chest pain, chills and fever, cryptococcosis, cyst, death, face edema, flu-like syndrome, hypothermia, injection site reaction, malaise, mucous membrane disorder, neck pain, overdose, photosensitivity reaction, sarcoma, sepsis

Cardiovascular System: cardiomyopathy, cardiovascular disorder, congestive heart failure, hypertension, hypotension, migraine, pallor, peripheral vascular disorder, phlebitis, postural hypotension, shock, syncope, tachycardia, vascular disorder, edema

Digestive System: cholangitis, colitis, constipation, esophagitis, dyspepsia, dysphagia, fecal incontinence, flatulence, gastritis, gastrointestinal hemorrhage, gingivitis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, abnormal liver function, liver damage, liver necrosis, melena, pancreatitis, proctitis, rectal disorder, stomatitis, aphthous stomatitis, tongue discoloration, mouth ulceration, tooth caries

Endocrine System: adrenal cortex insufficiency

Hemic & Lymphatic System: hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma like reaction, pancytopenia, splenic disorder, splenomegaly, thrombocytopenia, thrombocytopenic purpura

Metabolic & Nutritional System: cachexia, dehydration, edema, hypercalcemia, hyperglycemia, hyperkalemia, hyperlipemia, hypocalcemia, hypoglycemia, hypoglycemic reaction, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, increased alkaline phosphatase, increased BUN, increased lactic dehydrogenase, increased SGOT, increased SGPT, peripheral edema, respiratory alkalosis, thirst, weight loss, weight gain

Musculoskeletal System: arthralgia, arthrosis, bone necrosis, bone pain, joint disorder, leg cramps, myalgia, myasthenia, pathological fracture

Nervous System: abnormal dreams, abnormal gait, acute brain syndrome, agitation, amnesia, anxiety, ataxia, cerebrovascular disorder, confusion, convulsion, delirium, dementia, depression, dizziness, drug dependence, dry mouth, encephalopathy, facial paralysis, hallucinations, hemiplegia, hyperesthesia, hypertonia, hypotony, incoordination, increased libido, insomnia, myoclonus, nervousness, neuropathy, paresthesia, personality disorder, somnolence, speech disorder, tremor, twitching, vasodilatation, vertigo

Respiratory System: asthma, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, increased sputum, larynx edema, lung disorder, pharyngitis, pneumothorax, rhinitis, sinusitis

Skin & Appendages: acne, angioedema, dry skin, eczema, exfoliative dermatitis, furunculosis, herpes simplex, nail disorder, pruritus, rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin ulcer, sweating, urticaria

Special Senses: abnormal vision, amblyopia, blindness, cataract, conjunctivitis, corneal lesion, corneal opacity, diplopia, dry eyes, ear disorder, ear pain, eye disorder, eye pain, hyperacusis, iritis, keratitis, miosis, otitis externa, otitis media, refraction disorder, retinal detachment, retinal disorder, taste perversion, tinnitus, uveitis, visual field defect, hearing loss

Urogenital System: decreased creatinine clearance, dysuria, glycosuria, hematuria, kidney stone, mastitis, metorrhagia, nocturia, polyuria, prostatic disorder, toxic nephrophathy, urethritis, urinary casts, urinary incontinence, urinary retention, urinary tract infection

Table 5. All Clinical Adverse Events, Laboratory Abnormalities or Intercurrent Illnesses Regardless of Severity Occurring in > 15% of Patients

	N = 115* # patients (%)
* Patients receiving 5 mg/kg maintenance regimen in Studies 106 and 107.
Any Adverse Event	115	(100)
Proteinuria (≥ 30 mg/dL)	101	(88)
Nausea +/- Vomiting	79	(69)
Fever	67	(58)
Neutropenia (< 750 cells/mm3)	50	(43)
Asthenia	50	(43)
Headache	34	(30)
Rash	34	(30)
Infection	32	(28)
Alopecia	31	(27)
Diarrhea	30	(26)
Pain	29	(25)
Creatinine Elevation (> 1.5 mg/dL)	28	(24)
Anemia	28	(24)
Anorexia	26	(23)
Dyspnea	26	(23)
Chills	25	(22)
Increased Cough	22	(19)
Oral Moniliasis	21	(18)

Reporting of Adverse Reactions

Malignancies or serious adverse reactions that occur in patients who have received Vistide should be reported to Gilead in writing to the Director of Clinical Research, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 or by calling 1-800-GILEAD-5 (445-3235), or to FDA MedWatch 1-800-FDA-1088/fax 1-800-FDA-0178.

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Side Effects by Body System - for Healthcare Professionals

General

The major side effect associated with cidofovir therapy is renal toxicity. The most common adverse effects reported in clinical trials were proteinuria (50%), neutropenia (24%), decreased intraocular pressure (24%), decreased serum bicarbonate levels (16%), fever (14%), infection (12%), increased serum creatinine levels >= 2 mg/dL (12%), pneumonia (9%), dyspnea (8%), and nausea/vomiting (7%). The drug was discontinued in 39% of patients because of various adverse effects.

Renal

Renal side effects have included nephrotoxicity. It may be irreversible and is the major side effect associated with cidofovir therapy. Renal impairment, including cases of acute renal failure resulting in dialysis and/or contributing to death, has occurred with as few as one or two doses of the drug. Proteinuria (greater than 2+), reduced creatinine clearance (less than or equal to 55 mL/min), and/or elevations of serum creatinine concentration (greater than 0.4 mg/dL) occurred in about 59% of patients receiving a maintenance dose of 5 mg/kg every other week. Toxic nephropathy has also been reported.

Adequate hydration and concomitant administration of probenecid is essential to lessen the risk of renal toxicity associated with cidofovir. Proteinuria, as measured by urinalysis, may be an early indicator of cidofovir-associated nephrotoxicity. Serum creatinine concentrations and routine urinalysis should be monitored prior to each dose of cidofovir. In patients with proteinuria, intravenous hydration should be administered and the urinalysis repeated. Patients who have had previous therapy with foscarnet may be at increased risk of renal toxicity and should be monitored closely.

Ocular

The risk of ocular hypotony may be increased in patients with diabetes mellitus.

Uveitis or iritis was reported in 15 (11%) of 135 patients who were administered the 5 mg/kg maintenance dose. Patients should be monitored for signs and symptoms of these complications and if they develop, treatment with topical corticosteroids with or without topical cycloplegic agents may be useful.

Ocular side effects have included decreases intraocular pressure by more than 50% from baseline in 24% of patients in clinical trials; severe ocular hypotony (IOP less than 0.1 mmHg) occurred in 4%. Abnormal vision, amblyopia, blindness, cataract, conjunctivitis, corneal lesion, corneal opacity, diplopia, dry eyes, eye disorder, eye pain, iritis, keratitis, miosis, retinal detachment, retinal disorder, uveitis, and visual field defect have also been reported.

Metabolic

Metabolic side effects including a decreased serum bicarbonate level to less than or equal to 16 mEq/L (16%) and multiple abnormalities of proximal renal tubular function or Fanconi's syndrome (1%) have occurred. Cases of metabolic acidosis, in association with liver dysfunction and pancreatitis, which resulted in death have also been reported. Cachexia, dehydration, edema, hypercalcemia, hyperglycemia, hyperkalemia, hyperlipemia, hypocalcemia, hypoglycemia, hypoglycemic reaction, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, increased alkaline phosphatase, increased BUN, increased lactic dehydrogenase, increased SGOT, increased SGPT, peripheral edema, respiratory alkalosis, thirst, weight loss, and weight gain have also been observed in clinical trials. However, it could not be definitively determined from these trials that cidofovir was the causative agent.

Genitourinary

Genitourinary side effects have included dysuria, glycosuria, hematuria, kidney stone, mastitis, metrorrhagia, nocturia, polyuria, prostatic disorder, urethritis, urinary casts, urinary incontinence, urinary retention, and urinary tract infection, although a causal relationship to cidofovir was difficult to determine.

Hematologic

Hematologic side effects have included neutropenia, anemia, and thrombocytopenia. Hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma-like reaction, pancytopenia, splenic disorder, splenomegaly, thrombocytopenia, and thrombocytopenic purpura have also been reported but a causal relationship to cidofovir was difficult to determine.

Neutropenia (less than 500 cells/mm3) occurred in 24% of patients receiving cidofovir for CMV retinitis in clinical trials. Granulocyte colony-stimulating factor was used in 39% of patients to manage neutropenia due to cidofovir.

Hypersensitivity

Hypersensitivity or allergic reactions may include rash, fever, chills, and anaphylaxis. Patients receiving concomitant probenecid and cidofovir may experience hypersensitivity reactions caused by probenecid. Cidofovir and probenecid therapy should be discontinued in patients who experience severe systemic reactions.

Two patients developed erythroderma associated with concomitant administration of cidofovir and probenecid. Prophylactic or therapeutic use of antihistamines and/or acetaminophen may alleviate hypersensitivity reactions associated with the use of probenecid.

Gastrointestinal

Administration of probenecid after a meal and/or therapy with antiemetics may alleviate the nausea and vomiting associated with probenecid.

Gastrointestinal side effects such as nausea and/or vomiting have occurred in 69% of patients receiving concomitant probenecid and cidofovir for CMV retinitis. Diarrhea (26%), anorexia (23%), and abdominal pain (17%) also have been reported. Cholangitis, colitis, constipation, dysphagia, dyspepsia, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal hemorrhage, gingivitis, melena, pancreatitis, proctitis, rectal disorder, stomatitis, aphthous stomatitis, tongue discoloration, mouth ulceration, and tooth caries have also been reported; however, a causal relationship to cidofovir was difficult to determine.

Cardiovascular

Cardiovascular side effects such as cardiomyopathy, cardiovascular disorder, congestive heart failure, hypertension, hypotension, migraine, pallor, peripheral vascular disorder, postural hypotension, shock, syncope, tachycardia, vascular disorder, and edema have been reported from clinical trials. It was difficult, however, to prove a causal relationship to cidofovir because many of the studied patients had very advanced disease and were administered numerous concomitant medications.

Dermatologic

Dermatological side effects which included rash (30%) and alopecia (27%) were observed in clinical trials that included the use of probenecid. Acne, angioedema, dry skin, eczema, exfoliative dermatitis, furunculosis, herpes simplex, nail disorder, pruritus, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin ulcer, sweating, and urticaria have also been reported in clinical trials. It is important to note that these trials included patients with very advanced disease who were also taking numerous concomitant medications, therefore, a causal relationship to cidofovir was difficult to determine.

Local

Phlebitis has been reported with the use of intravenous cidofovir.

Endocrine

Endocrine adverse effects are not common. Adrenal cortex insufficiency has been reported, although, a direct causal relationship to cidofovir was not determined.

Hepatic

Hepatic adverse effects are not common. Hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, abnormal liver function, liver damage, and liver necrosis were reported in clinical trials although a causal relationship to cidofovir was difficult to determine due to the fact that most of the patients received many concomitant medications and due to the broad manifestations of the underlying disease.

Musculoskeletal

Musculoskeletal side effects which have been reported in clinical trials regardless of the relationship to cidofovir or probenecid include arthralgia, asthenia, arthrosis, bone necrosis, bone pain, joint disorder, leg cramps, myalgia, myasthenia, back pain, neck pain, and pathological fracture.

Nervous system

Nervous system side effects have included abnormal dreams, abnormal gait, acute brain syndrome, agitation, amnesia, anxiety, ataxia, cerebrovascular disorder, confusion, convulsion, delirium, dementia, depression, dizziness, drug dependence, dry mouth, encephalopathy, facial paralysis, hallucinations, headache, hemiplegia, hyperesthesia, hypertonia, hypotony, incoordination, increased libido, insomnia, myoclonus, nervousness, neuropathy, paresthesia, personality disorder, somnolence, speech disorder, tremor, twitching, vasodilatation, and vertigo. A definitive causal relationship to cidofovir was difficult to make, however, from these trials.

Oncologic

Oncologic side effects have not been observed in humans. In a 26-week animal study, however, cidofovir was found to be carcinogenic in rats.

Respiratory

Respiratory side effects such as asthma, bronchitis, dyspnea, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, increased sputum, larynx edema, lung disorder, pharyngitis, pneumonia, pneumothorax, rhinitis, sinusitis, and increased cough have been reported in clinical trials, however, a causal relationship to cidofovir was difficult to determine.

Other

Other side effects reported in clinical trials regardless of the relationship to cidofovir or probenecid were flu-like syndrome, hypothermia, malaise, mucous membrane disorder, photosensitivity reaction, sarcoma, infection, sepsis, oral moniliasis, taste perversion, ear disorder, ear pain, hyperacusis, otitis externa, otitis media, tinnitus, and hearing loss.

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