Cytovene-IV

ganciclovir sodium

Dosage Form: injection, powder, lyophilized, for solution
CYTOVENE®-IV

(ganciclovir sodium for injection)

FOR INTRAVENOUS INFUSION ONLY

WARNING

THE CLINICAL TOXICITY OF Cytovene-IV INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.

Cytovene-IV IS INDICATED FOR USE ONLY IN THE TREATMENT OF CYTOMEGALOVIRUS (CMV) RETINITIS IN IMMUNOCOMPROMISED PATIENTS AND FOR THE PREVENTION OF CMV DISEASE IN TRANSPLANT PATIENTS AT RISK FOR CMV DISEASE (see INDICATIONS AND USAGE).

Cytovene-IV Description

Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV). Cytovene-IV is the brand name for ganciclovir sodium for injection.

Cytovene-IV is available as sterile lyophilized powder in strength of 500 mg per vial for intravenous administration only. Each vial of Cytovene-IV contains the equivalent of 500 mg ganciclovir as the sodium salt (46 mg sodium). Reconstitution with 10 mL of Sterile Water for Injection, USP, yields a solution with pH 11 and a ganciclovir concentration of approximately 50 mg/mL. Further dilution in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION).

Ganciclovir is a white to off-white crystalline powder with a molecular formula of C9H13N504 and a molecular weight of 255.23. The chemical name for ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine. Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022. The pKas for ganciclovir are 2.2 and 9.4.

Ganciclovir, when formulated as monosodium salt in the IV dosage form, is a white to off-white lyophilized powder with the molecular formula of C9H12N5Na04, and a molecular weight of 277.22. The chemical name for ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The lyophilized powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

The chemical structures of ganciclovir sodium and ganciclovir are:

ganciclovir sodium                                                                     ganciclovir

All doses in this insert are specified in terms of ganciclovir.

VIROLOGY

Mechanism of Action

Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human clinical studies.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation into viral DNA, resulting in eventual termination of viral DNA elongation.

Antiviral Activity

The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 µg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 30 to 725 µg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC50 0.028 to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Clinical Antiviral Effect of Cytovene-IV and Ganciclovir Capsules

Cytovene-IV

In a study of Cytovene-IV treatment of life- or sight-threatening CMV disease in immunocompromised patients, 121 of 314 patients had CMV cultured within 7 days prior to treatment and sequential posttreatment viral cultures of urine, blood, throat and/or semen. As judged by conversion to culture negativity, or a greater than 100-fold decrease in in vitro CMV titer, at least 83% of patients had a virologic response with a median response time of 7 to 15 days.

Antiviral activity of Cytovene-IV was demonstrated in two randomized studies for the prevention of CMV disease in transplant recipients (see Table 1).

Table 1 Patients With Positive CMV Cultures

	Heart Allograft* (n = 147)		Bone Marrow Allograft (n = 72)
Time	Cytovene-IV†	Placebo	Cytovene-IV‡	Placebo
* CMV seropositive or receiving graft from seropositive donor † 5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for 14 days ‡ 5 mg/kg bid for 7 days followed by 5 mg/kg qd until day 100 posttransplant
Pretreatment	1/67     (2%)	5/64     (8%)	37/37   (100%)	35/35   (100%)
Week 2	2/75     (3%)	11/67   (16%)	2/31     (6%)	19/28   (68%)
Week 4	3/66     (5%)	28/66   (43%)	0/24     (0%)	16/20   (80%)

Ganciclovir Capsules

In trials comparing Cytovene-IV with Ganciclovir capsules for the maintenance treatment of CMV retinitis in patients with AIDS, serial urine cultures and other available cultures (semen, biopsy specimens, blood and others) showed that a small proportion of patients remained culture-positive during maintenance therapy with no statistically significant differences in CMV isolation rates between treatment groups.

Viral Resistance

The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50 >3.0 µg/mL (12.0 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with Cytovene-IV. In a controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 gene of CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir.

Cytovene-IV - Clinical Pharmacology

Pharmacokinetics

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR Cytovene-IV. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

Absorption

At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 µg∙hr/mL (n=16) and Cmax ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).

Distribution

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h ranged from 0.31 to 0.68 µg/mL representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Elimination

When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was recovered unmetabolized in the urine. Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). Half-life was 3.5 ± 0.9 hours (n=98) following IV administration and 4.8 ± 0.9 hours (n=39) following oral administration.

Special Populations

Renal Impairment

The pharmacokinetics following intravenous administration of Cytovene-IV solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg.

Table 2 Pharmacokinetics of Patients with Renal Impairment

Estimated Creatinine Clearance (mL/min)	n	Dose	Clearance (mL/min) Mean ± SD	Half-life (hours) Mean ± SD
50-79	4	3.2-5 mg/kg	128 ± 63	4.6 ± 1.4
25-49	3	3-5 mg/kg	57 ± 8	4.4 ± 0.4
<25	3	1.25-5 mg/kg	30 ± 13	10.7 ± 5.7

Based on these observations, it is necessary to modify the dosage of ganciclovir in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous administration.

Race/Ethnicity and Gender

The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen of 1000 mg every 8 hours. Although the numbers of blacks (16%) and Hispanics (20%) were small, there appeared to be a trend towards a lower steady-state Cmax and AUC0-8 in these subpopulations as compared to Caucasians. No definitive conclusions regarding gender differences could be made because of the small number of females (12%); however, no differences between males and females were observed.

Pediatrics

Ganciclovir pharmacokinetics were studied in 27 neonates, aged 2 to 49 days. At an intravenous dose of 4 mg/kg (n=14) or 6 mg/kg (n=13), the pharmacokinetic parameters were, respectively, Cmax of 5.5 ± 1.6 and 7.0 ± 1.6 µg/mL, systemic clearance of 3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and t½ of 2.4 hours (harmonic mean) for both.

Ganciclovir pharmacokinetics were also studied in 10 pediatric patients, aged 9 months to 12 years. The pharmacokinetic characteristics of ganciclovir were the same after single and multiple (q12h) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 ± 0.22 L/kg, Cmax was 7.9 ± 3.9 µg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t½ was 2.4 ± 0.7 hours. The pharmacokinetics of intravenous ganciclovir in pediatric patients are similar to those observed in adults.

Elderly

No studies have been conducted in adults older than 65 years of age.

Indications and Usage for Cytovene-IV

Cytovene-IV is indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Cytovene-IV is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease (see CLINICAL TRIALS).

SAFETY AND EFFICACY OF Cytovene-IV HAVE NOT BEEN ESTABLISHED FOR CONGENITAL OR NEONATAL CMV DISEASE; NOR FOR THE TREATMENT OF ESTABLISHED CMV DISEASE OTHER THAN RETINITIS; NOR FOR USE IN NON-IMMUNOCOMPROMISED INDIVIDUALS.

Clinical Trials

1. Treatment of CMV Retinitis

The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions. The diagnosis of CMV retinitis may be supported by culture of CMV from urine, blood, throat or other sites, but a negative CMV culture does not rule out CMV retinitis.

Studies With Cytovene-IV

In a retrospective, non-randomized, single-center analysis of 41 patients with AIDS and CMV retinitis diagnosed by ophthalmologic examination between August 1983 and April 1988, treatment with Cytovene-IV solution resulted in a significant delay in mean (median) time to first retinitis progression compared to untreated controls [105 (71) days from diagnosis vs 35 (29) days from diagnosis]. Patients in this series received induction treatment of Cytovene-IV 5 mg/kg bid for 14 to 21 days followed by maintenance treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week (see DOSAGE AND ADMINISTRATION).

In a controlled, randomized study conducted between February 1989 and December 1990,1 immediate treatment with Cytovene-IV was compared to delayed treatment in 42 patients with AIDS and peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-treatment group and 22 in the delayed-treatment group) were included in the analysis of time to retinitis progression. Based on masked assessment of fundus photographs, the mean [95% CI] and median [95% CI] times to progression of retinitis were 66 days [39, 94] and 50 days [40, 84], respectively, in the immediate-treatment group compared to 19 days [11, 27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.

Studies Comparing Ganciclovir Capsules to Cytovene-IV

Table 3 Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034

		ICM 1653 (n=121)	ICM 1774 (n=225)	AVI 034 (n=159)
Median age (years) Range		38 24-62	37 22-56	39 23-62
Sex	Males	116 (96%)	222 (99%)	148 (93%)
	Females	5 (4%)	3 (1%)	10 (6%)
	Asian	3 (3%)	5 (2%)	7 (4%)
Ethnicity	Black	11 (9%)	9 (4%)	3 (2%)
	Caucasian	98 (81%)	186 (83%)	140 (88%)
	Other	9 (7%)	25 (11%)	8 (5%)
Median CD4 Count Range		9.5 0-141	7.0 0-80	10.0 0-320
Mean (SD) Observation Time (days)		107.9 (43.0)	97.6 (42.5)	80.9 (47.0)

ICM 1653

In this randomized, open-label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received a 3-week induction course of Cytovene-IV solution, 5 mg/kg bid for 14 days followed by 5 mg/kg once daily for 1 additional week.2 Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either Cytovene-IV solution, 5 mg/kg once daily, or ganciclovir capsules, 500 mg 6 times daily (3000 mg/day). The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43], respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -5 days [-22, 12]. See Figure 1 for comparison of the proportion of patients remaining free of progression over time.

ICM 1774

In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August 1993, patients with AIDS and stable CMV retinitis following from 4 weeks to 4 months of treatment with Cytovene-IV solution were randomized to receive maintenance treatment with Cytovene-IV solution, 5 mg/kg once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules, 1000 mg tid for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -12 days [-24, 0]. See Figure 2 for comparison of the proportion of patients remaining free of progression over time.

AVI 034

In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with Cytovene-IV, 5 mg/kg twice daily, were randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg 6 times daily or Cytovene-IV solution, 5 mg/kg/day.3 The mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -11 days [-24, 1]. See Figure 3 for comparison of the proportion of patients remaining free of progression over time.

Comparison of other CMV retinitis outcomes between oral and IV formulations (development of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive, showed no marked differences between treatment groups in these studies. Because of low event rates among these endpoints, these studies are underpowered to rule out significant differences in these endpoints.

Figure 1             ICM 1653

Figure 2             ICM 1774

Figure 3             AVI 034

2. Prevention of CMV Disease in Transplant Recipients

Cytovene-IV was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

ICM 1496

In a randomized, double-blind, placebo-controlled study of 149 heart transplant recipients4 at risk for CMV infection (CMV seropositive or a seronegative recipient of an organ from a CMV seropositive donor), there was a statistically significant reduction in the overall incidence of CMV disease in patients treated with Cytovene-IV. Immediately posttransplant, patients received Cytovene-IV solution 5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with Cytovene-IV vs 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day posttransplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups (refer to Table 6 in ADVERSE EVENTS).

ICM 1689

In a randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients5 with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was a statistically significant reduction in the incidence of CMV disease in patients treated with Cytovene-IV following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received Cytovene-IV solution 5 mg/kg bid for 7 days followed by 5 mg/kg qd through day 100 posttransplant. One of the 37 (3%) patients treated with Cytovene-IV vs 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At 6 months posttransplant, there continued to be a statistically significant reduction in the incidence of CMV disease in patients treated with Cytovene-IV. Six of 37 (16%) patients treated with Cytovene-IV vs 15 of the 35 (43%) placebo-treated patients developed disease through 6 months posttransplant. The overall rate of survival was statistically significantly higher in the group treated with Cytovene-IV, both at day 100 and day 180 posttransplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with Cytovene-IV (refer to Table 6 in ADVERSE EVENTS).

ICM 1570

A second, randomized, unblinded study evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease.6 Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 posttransplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with Cytovene-IV solution (5 mg/kg bid for 14 days followed by 5 mg/kg qd 5 days/week until day 120). Four of 20 (20%) patients treated with Cytovene-IV and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was significantly lower in the group treated with Cytovene-IV, consistent with the results observed in ICM 1689.

Contraindications

Cytovene-IV is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir.

Warnings

Hematologic

Cytovene-IV should not be administered if the absolute neutrophil count is less than 500 cells/µL or the platelet count is less than 25,000 cells/µL. Granulocytopenia (neutropenia), anemia and thrombocytopenia have been observed in patients treated with Cytovene-IV. The frequency and severity of these events vary widely in different patient populations (see ADVERSE EVENTS).

Cytovene-IV should, therefore, be used with caution in patients with pre-existing cytopenias or with a history of cytopenic reactions to other drugs, chemicals or irradiation. Granulocytopenia usually occurs during the first or second week of treatment but may occur at any time during treatment. Cell counts usually begin to recover within 3 to 7 days of discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Cytovene-IV solution for treatment of CMV retinitis.

Impairment of Fertility

Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses (see PRECAUTIONS: Carcinogenesis, Mutagenesis1 and Impairment of Fertility1). Although data in humans have not been obtained regarding this effect, it is considered probable that ganciclovir at the recommended doses causes temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur.

Teratogenesis

Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Cytovene-IV (see PRECAUTIONS: Pregnancy1: Category C).

Precautions

General

In clinical studies with Cytovene-IV, the maximum single dose administered was 6 mg/kg by intravenous infusion over 1 hour. Larger doses have resulted in increased toxicity. It is likely that more rapid infusions would also result in increased toxicity (see OVERDOSAGE). Administration of Cytovene-IV solution should be accompanied by adequate hydration.

Initially reconstituted solutions of Cytovene-IV have a high pH (pH 11). Despite further dilution in intravenous fluids, phlebitis and/or pain may occur at the site of intravenous infusion. Care must be taken to infuse solutions containing Cytovene-IV only into veins with adequate blood flow to permit rapid dilution and distribution (see DOSAGE AND ADMINISTRATION).

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED FOR Cytovene-IV. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION).

Information for Patients

All patients should be informed that the major toxicities of ganciclovir are granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Patients should be informed that ganciclovir has been associated with elevations in serum creatinine.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with Cytovene-IV. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Cytovene-IV.

Patients should be advised that ganciclovir causes tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

All HIV+ Patients

These patients may be receiving zidovudine. Patients should be counseled that treatment with both ganciclovir and zidovudine simultaneously may not be tolerated by some patients and may result in severe granulocytopenia (neutropenia). Patients with AIDS may be receiving didanosine. Patients should be counseled that concomitant treatment with both ganciclovir and didanosine can cause didanosine serum concentrations to be significantly increased.

HIV+ Patients With CMV Retinitis

Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may continue to experience progression of retinitis during or following treatment. Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with Cytovene-IV. Some patients will require more frequent follow-up.

Transplant Recipients

Transplant recipients should be counseled regarding the high frequency of impaired renal function in transplant recipients who received Cytovene-IV solution in controlled clinical trials, particularly in patients receiving concomitant administration of nephrotoxic agents such as cyclosporine and amphotericin B. Although the specific mechanism of this toxicity, which in most cases was reversible, has not been determined, the higher rate of renal impairment in patients receiving Cytovene-IV solution compared with those who received placebo in the same trials may indicate that Cytovene-IV played a significant role.

Laboratory Testing

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Cytovene-IV (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Increased serum creatinine levels have been observed in trials evaluating Cytovene-IV. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Didanosine

When the standard intravenous ganciclovir induction dose (5 mg/kg infused over 1 hour every 12 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, the steady-state didanosine AUC0-12 increased 70 ± 40% (range: 3% to 121%, n=11) and Cmax increased 49 ± 48% (range: -28% to 125%). In a separate study, when the standard intravenous ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, didanosine AUC0-12 increased 50 ± 26% (range: 22% to 110%, n=11) and Cmax increased 36 ± 36% (range: -27% to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC12-24) were unchanged during the dosing intervals when ganciclovir was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug.

Zidovudine

At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir AUC0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n=12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range: -11% to 74%) in the presence of ganciclovir. No drug-drug interaction studies have been conducted with IV ganciclovir and zidovudine.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage.

Probenecid

At an oral dose of 1000 mg of ganciclovir every 8 hours (n=10), ganciclovir AUC0-8 increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion. No drug-drug interaction studies have been conducted with IV ganciclovir and probenecid.

Imipenem-cilastatin

Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Other Medications

It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

No formal drug interaction studies of Cytovene-IV and drugs commonly used in transplant recipients have been conducted. Increases in serum creatinine were observed in patients treated with Cytovene-IV plus either cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity (see ADVERSE EVENTS). In a retrospective analysis of 93 liver allograft recipients receiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral cyclosporine (at therapeutic doses), there was no evidence of an effect on cyclosporine whole blood concentrations.

Carcinogenesis, Mutagenesis1

Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1× and 1.4×, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20 mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 µg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (IV) (2.8 to 10× human exposure based on AUC) but not 50 mg/kg (exposure approximately comparable to the human based on AUC). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 µg/mL.

Impairment of Fertility1

Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose.

Pregnancy1

Category C

Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2× the human exposure based on AUC comparisons), respectively. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.

Daily intravenous doses of 90 mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach (see Carcinogenesis, Mutagenesis1). The drug exposure in mice as estimated by the AUC was approximately 1.7× the human AUC.

Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. Cytovene-IV should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

1

Footnote: All dose comparisons presented in the Carcinogenesis, Mutagenesis1, Impairment of Fertility1, and Pregnancy1 subsections are based on the human AUC following administration of a single 5 mg/kg intravenous infusion of Cytovene-IV as used during the maintenance phase of treatment. Compared with the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction phase (5 mg/kg bid). The cross-species dose comparisons should be divided by 2 for intravenous induction treatment with Cytovene-IV.

Nursing Mothers

It is not known whether ganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely (see Pregnancy1: Category C). Mothers should be instructed to discontinue nursing if they are receiving Cytovene-IV. The minimum interval before nursing can safely be resumed after the last dose of Cytovene-IV is unknown.

Pediatric Use

SAFETY AND EFFICACY OF Cytovene-IV IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED. THE USE OF Cytovene-IV IN THE PEDIATRIC POPULATION WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY OF LONG-TERM CARCINOGENICITY AND REPRODUCTIVE TOXICITY. ADMINISTRATION TO PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN ONLY AFTER CAREFUL EVALUATION AND ONLY IF THE POTENTIAL BENEFITS OF TREATMENT OUTWEIGH THE RISKS.

The spectrum of adverse events reported in 120 immunocompromised pediatric clinical trial participants with serious CMV infections receiving Cytovene-IV solution were similar to those reported in adults. Granulocytopenia (17%) and thrombocytopenia (10%) were the most common adverse events reported.

Sixteen pediatric patients (8 months to 15 years of age) with life- or sight-threatening CMV infections were evaluated in an open-label, Cytovene-IV solution, pharmacokinetics study. Adverse events reported for more than one pediatric patient were as follows: hypokalemia (4/16, 25%), abnormal kidney function (3/16, 19%), sepsis (3/16, 19%), thrombocytopenia (3/16, 19%), leukopenia (2/16, 13%), coagulation disorder (2/16, 13%), hypertension (2/16, 13%), pneumonia (2/16, 13%) and immune system disorder (2/16, 13%).

There has been very limited clinical experience using Cytovene-IV for the treatment of CMV retinitis in patients under the age of 12 years. Two pediatric patients (ages 9 and 5 years) showed improvement or stabilization of retinitis for 23 and 9 months, respectively. These pediatric patients received induction treatment with 2.5 mg/kg tid followed by maintenance therapy with 6 to 6.5 mg/kg once per day, 5 to 7 days per week. When retinitis progressed during once-daily maintenance therapy, both pediatric patients were treated with the 5 mg/kg bid regimen. Two other pediatric patients (ages 2.5 and 4 years) who received similar induction regimens showed only partial or no response to treatment. Another pediatric patient, a 6-year-old with T-cell dysfunction, showed stabilization of retinitis for 3 months while receiving continuous infusions of Cytovene-IV at doses of 2 to 5 mg/kg/24 hours. Continuous infusion treatment was discontinued due to granulocytopenia.

Eleven of the 72 patients in the placebo-controlled trial in bone marrow transplant recipients were pediatric patients, ranging in age from 3 to 10 years (5 treated with Cytovene-IV and 6 with placebo). Five of the pediatric patients treated with Cytovene-IV received 5 mg/kg intravenously bid for up to 7 days; 4 patients went on to receive 5 mg/kg qd up to day 100 posttransplant. Results were similar to those observed in adult transplant recipients treated with Cytovene-IV. Two of the 6 placebo-treated pediatric patients developed CMV pneumonia vs none of the 5 patients treated with Cytovene-IV. The spectrum of adverse events in the pediatric group was similar to that observed in the adult patients.

Geriatric Use

The pharmacokinetic profiles of Cytovene-IV in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of Cytovene-IV (see DOSAGE AND ADMINISTRATION).

Clinical studies of Cytovene-IV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Cytovene-IV is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Use in Patients With Renal Impairment and DOSAGE AND ADMINISTRATION).

Use in Patients With Renal Impairment

Cytovene-IV should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance (see DOSAGE AND ADMINISTRATION and ADVERSE EVENTS).

Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately 50%.

ADVERSE EVENTS

Adverse events that occurred during clinical trials of Cytovene-IV solution are summarized below, according to the participating study subject population.

Subjects With AIDS

Three controlled, randomized, phase 3 trials comparing Cytovene-IV and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Cytovene-IV or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse events. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data

Table 4 Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis

Amevive

Dosage Form: intramuscular injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Amevive

Amevive® is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

Amevive Dosage and Administration

Dosing Instructions

The recommended dose of Amevive® is 15 mg intramuscularly once weekly for 12 weeks. The CD4+ T lymphocyte counts should be measured before initiating dosing.

Amevive® therapy should not be initiated in patients who have CD4+ T lymphocyte counts below normal. The CD4+ T lymphocyte counts of patients receiving Amevive® should be monitored every two weeks throughout the course of the 12-week dosing regimen. If CD4+ T lymphocyte counts are below 250 cells/µL, Amevive® dosing should be withheld and weekly monitoring instituted. Amevive® should be discontinued if the counts remain below 250 cells/µL for one month [seeWarnings and Precautions (5.1)].

An additional 12-week course may be initiated if at least 12-weeks have passed since the previous treatment course and the CD4+ T lymphocyte counts are normal.

Preparation Instructions

• Amevive® should be reconstituted using aseptic technique. Each vial is for single patient use only.


• Amevive® 15 mg lyophilized powder should only be reconstituted with the supplied diluent (Sterile Water for Injection


• Do not add other medications to solutions containing Amevive®. Do not filter reconstituted solution during preparation or administration.


• Using the supplied syringe and one of the supplied needles, withdraw 0.6 mL  of the diluent. Keeping the needle pointed at the sidewall of the vial, slowly inject the diluent into the vial of Amevive®. Foaming will occur. Gently swirl the contents during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. Dissolution of Amevive® generally takes less than two minutes.


• Inspect Amevive® reconstituted solution visually for particulate matter and discoloration. Amevive® reconstituted solution should be clear and colorless to slightly yellow. The solution should not be used if it is cloudy, if there is pronounced discoloration, or if particulate matter is present.


• The reconstituted product should be used immediately or within 4 hours if stored in the vial at 2-8°C (36-46°F). Discard Amevive® not used within 4 hours of reconstitution.

Administration Instructions

• The reconstituted solution should be clear and colorless to slightly yellow. Do not administer the solution if cloudy or discolored or if undissolved material or particulate matter is present.


• Remove the needle used for reconstitution and attach the other supplied needle. Withdraw 0.5 mL of the Amevive® solution into the syringe,  and inject the full 0.5 mL of solution intramuscularly. A volume of 0.5 mL of the reconstituted solution contains 15 mg of alefacept.  Rotate injection sites so that a different site is used for each new injection. New injections should be given at least one inch from a previous injection site and never into tender, bruised, erythematous, or indurated skin.


• Discard empty vials of Amevive®.

Dosage Forms and Strengths

For injection; Amevive® is supplied as 15 mg of lyophilized powder in a single-use vial for reconstitution with Sterile Water for Injection, USP.

Contraindications

Amevive® should not be administered to patients infected with HIV. Amevive® reduces CD4+ T lymphocyte counts, which might accelerate disease progression or increase complications of disease in these patients [see Warnings and Precautions (5.1, 5.3)].

Warnings and Precautions

Lymphopenia

Amevive® induces dose-dependent reductions in circulating CD4+ and CD8+ T lymphocyte counts. CD4+ counts should be normal before initiating treatment with Amevive® and should be closely monitored during Amevive® treatment [see Dosage and Administration (2.1)]

Malignancies

Amevive® may increase the risk of malignancies. Malignancies were reported in subjects who received Amevive® in clinical studies [see Adverse Reactions (6.1, 6.3)].

In preclinical studies, animals developed B cell hyperplasia, and one animal developed a lymphoma [seeNonclinical Toxicology (13.1)]. Amevive® should not be administered to patients with a history of systemic malignancy.

Exercise caution when considering the use of Amevive® in patients at high risk for malignancy. Discontinue Amevive® if a patient develops a malignancy.

Serious Infections

Amevive® is an immunosuppressive agent and, therefore, has the potential to increase the risk of infection and reactivate latent, chronic infections. Serious infections (infections requiring hospitalization) were reported in subjects who received Amevive® [see Adverse Reactions (6.1, 6.3)]. Amevive® should not be administered to patients with a clinically important infection. Exercise caution when considering the use of Amevive® in patients with chronic infections or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection during or after a course of Amevive®. New infections should be closely monitored. If a patient develops a serious infection, Amevive® should be discontinued [see Adverse Reactions (6.1)].

Concomitant Therapies

Patients receiving other immunosuppressive agents or phototherapy should not receive concurrent therapy with Amevive® because of the possibility of excessive immunosuppression.

Immunizations

The safety and efficacy of live or live-attenuated vaccines in patients being treated with Amevive® have not been studied. In a study of 46 patients with chronic plaque psoriasis, the ability to mount immunity to tetanus toxoid (recall antigen) and an experimental neo-antigen was preserved in those patients undergoing Amevive® therapy.

Hypersensitivity Reactions

Urticaria and angioedema have been associated with the administration of Amevive®. If an anaphylactic reaction or other serious allergic reaction occurs, discontinue Amevive® immediately and initiate appropriate therapy.

Hepatic Injury

In post-marketing experience there have been reports of liver injury, including asymptomatic transaminase elevation, fatty infiltration of the liver, hepatitis, decompensation of cirrhosis with liver failure, and acute liver failure. Liver failure has been reported with concomitant alcohol use [see Adverse Reactions (6.3)]. In the 24-week period constituting the first course of placebo-controlled studies, 1.7% (15/876) of Amevive®-treated patients and 1.2% (5/413) of the placebo group experienced ALT and/or AST elevations of at least 3 times the upper limit of normal. While the exact relationship of these occurrences with the use of Amevive® has not been established, patients with signs or symptoms of liver injury should be fully evaluated. Amevive® should be discontinued in patients who develop clinical signs of liver injury.

Adverse Reactions

The most serious adverse reactions described elsewhere in the labeling include the following:

• Lymphopenia [see Warnings and Precautions (5.1)]


• Malignancies [see Warnings and Precautions (5.2)]


• Serious Infections requiring hospitalization [see Warnings and Precautions (5.3)]


• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
  

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Commonly observed adverse events seen in the first course of placebo-controlled clinical trials with at least a 2% higher incidence in the Amevive® -treated patients compared to placebo-treated patients were: pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury. The only adverse event that occurred at a 5% or higher incidence among Amevive®-treated patients compared to placebo-treated patients was chills (1% placebo vs. 6% Amevive®), which occurred predominantly with intravenous administration.

The adverse reactions which most commonly resulted in clinical intervention were cardiovascular events including coronary artery disorder in <1% of subjects and myocardial infarct in <1% of subjects. These events were not observed in any of the 413 placebo-treated subjects. The total number of subjects hospitalized for cardiovascular events in the Amevive®-treated group was 1.2% (11/876).

The most common events resulting in discontinuation of treatment with Amevive® were CD4+ T lymphocyte levels below 250 cells/µL [see Warnings and Precautions (5.1)], headache (0.2%), and nausea (0.2%).

The data described below reflect exposure to Amevive® in a total of 1869 psoriasis patients, of whom 1315 (70%) received 1 to 2 courses of therapy and 554 (30%) received 3 or more courses. The median duration of follow-up was 8.4 months for the patients who received 1 to 2 courses and 27.7 months for the patients who received 3 or more courses of Amevive®. Of the 1869 total patients, 876 received their first course in placebo-controlled studies. The population studied ranged in age from 16 to 84 years, and included 69% men and 31% women. The patients were mostly Caucasian (88%), reflecting the general psoriatic population. Disease severity at baseline was moderate to severe psoriasis.

Effect on Lymphocyte Counts

In the intramuscular study (Study 2), 4% of patients temporarily discontinued treatment and no patients permanently discontinued treatment due to CD4+ T lymphocyte counts below the specified threshold of 250 cells/µL. In Study 2, 10%, 28%, and 42% of patients had total lymphocyte, CD4+, and CD8+ T lymphocyte counts below normal, respectively. Twelve weeks after a course of therapy (12 weekly doses), 2%, 8%, and 21% of patients had total lymphocyte, CD4+, and CD8+ T cell counts below normal.

In the first course of the intravenous study (Study 1), 10% of patients temporarily discontinued treatment and 2% permanently discontinued treatment due to CD4+ T lymphocyte counts below the specified threshold of 250 cells/µL. During the first course of Study 1, 22% of patients had total lymphocyte counts below normal, 48% had CD4+ T lymphocyte counts below normal and 59% had CD8+ T lymphocyte counts below normal. The maximal effect on lymphocytes was observed within 6 to 8 weeks of initiation of treatment. Twelve weeks after a course of therapy (12 weekly doses), 4% of patients had total lymphocyte counts below normal, 19% had CD4+ T lymphocyte counts below normal, and 36% had CD8+ T lymphocyte counts below normal.

For patients receiving a second course of Amevive® in Study 1, 17% of patients had total lymphocyte counts below normal, 44% had CD4+ T lymphocyte counts below normal, and 56% had CD8+ T lymphocyte counts below normal. Twelve weeks after completing dosing, 3% of patients had total lymphocyte counts below normal, 17% had CD4+ T lymphocyte counts below normal, and 35% had CD8+ T lymphocyte counts below normal [see Warnings and Precautions (5.7)].

In an open-label postmarketing study, subjects with psoriasis were treated with up to three courses of Amevive: each course consisted of Amevive 15 mg intramuscular weekly for twelve weeks, followed by twelve weeks of observation. Lymphocyte counts were assessed at regular intervals during the post-treatment observation period. For subjects whose counts went below 75% of the baseline at any time after the last dose in the study, the time from the last dose to the time that their lymphocyte count returned to ≥ 75% of baseline was analyzed. Of 115 evaluable subjects for total lymphocyte counts, the median time of recovery was 2.1 months with a range of 0.6 to 11.1 months. Of the 123 evaluable subjects for CD4+ T cell counts, the median time to recovery was 2.3 months with the range of 0.6 to 12.4 months. Of the 105 evaluable subjects for CD8+ T cell counts, the median time to recovery was 1.6 months with a range of 0.6 to 8.7 months.

Malignancies

In the 24-week period constituting the first course of placebo-controlled studies, 13 malignancies were diagnosed in 11 Amevive®-treated patients. The incidence of malignancies was 1.3% (11/876) for Amevive®-treated patients compared to 0.5% (2/413) in the placebo group.

Among 1869 patients who received Amevive® at any dose in clinical trials, 43 patients were diagnosed with 63 treatment-emergent malignancies. The majority of the malignancies were non-melanoma skin cancers: 46 cases (20 basal cell, 26 squamous cell carcinomas) in 27 patients. Other malignancies observed in Amevive®-treated patients included melanoma (n=3), solid organ malignancies (n=12 in 11 patients), and lymphomas (n=5); the latter consisted of two Hodgkin’s and two non-Hodgkin’s lymphomas, and one cutaneous T cell lymphoma (mycosis fungoides).

Infections

In the 24-week period constituting the first course of placebo-controlled studies, serious infections (infections requiring hospitalization) were seen at a rate of 0.9% (8/876) in Amevive®-treated patients and 0.2% (1/413) in the placebo group. In patients receiving repeated courses of Amevive® therapy, the rates of serious infections remained similar across courses of therapy. Serious infections among 1869 Amevive®-treated patients included cellulitis, abscesses, wound infections, toxic shock, pneumonia, appendicitis, cholecystitis, gastroenteritis and herpes infections.

Hypersensitivity Reactions

In clinical studies, 4 of 1869 (0.2%) patients were reported to experience angioedema: two of these patients were hospitalized. In the 24-week period constituting the first course of placebo-controlled studies, urticaria was reported in 6 (<1%) Amevive®-treated patients vs. 1 patient in the control group. Urticaria resulted in discontinuation of therapy in one of the Amevive®-treated patients.

Hepatic Injury

In the 24-week period constituting the first course of placebo-controlled studies, 1.7% (15/876) of Amevive®-treated patients and 1.2% (5/413) of the placebo group experienced ALT and/or AST elevations of at least 3 times the upper limit of normal.

Injection Site Reactions

In the intramuscular study (Study 2), 16% of Amevive®-treated patients and 8% of placebo-treated patients reported injection site reactions. In patients receiving repeated courses of Amevive® intramuscular therapy, the incidence of injection site reactions remained similar across courses of therapy. Reactions at the site of injection were generally mild, typically occurred on single occasions, and included either pain (7%), inflammation (4%), bleeding (4%), edema (2%), non-specific reaction (2%), mass (1%), or skin hypersensitivity (<1%). In the clinical trials, a single case of injection site reaction led to the discontinuation of Amevive®.

Immunogenicity

Approximately 3% (40/1357) of patients receiving Amevive® developed low-titer antibodies to alefacept as determined by an ELISA. When anti-alefacept antibodies were assessed using a dual specificity Biacore assay, 72% (72/100) of patients receiving Amevive® were positive for anti-alefacept antibodies. The long-term immunogenicity of Amevive® is unknown.

Results are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alefacept with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Amevive. Because these reactions are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Malignancies

In post-marketing experience there have been reports of malignancies including skin, solid organ, lymphomas and leukemia [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Serious Infections

In post-marketing experience there have been reports of infections including sepsis, opportunistic infections (viral, fungal, bacterial), cellulitis, urinary tract infection (UTI), Clostridium difficile colitis and pharyngitis [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Hepatic Injury

In post-marketing experience there have been reports of asymptomatic transaminase elevation, fatty infiltration of the liver, hepatitis, and severe liver failure [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Drug Interactions

Drug interaction studies have not been conducted with Amevive®.

Concomitant Therapies

The safety of Amevive® in combination with immunosuppressive agents or phototherapy has not been evaluated [see Warnings and Precautions (5.4)].

CYP450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, a molecule that exerts its pharmacological effect by inhibiting the release of cytokines, such as Amevive®, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of Amevive® in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Women of childbearing potential make up a considerable segment of the patient population affected by psoriasis. Since the effect of Amevive® on pregnancy and fetal development, including immune system development, is not known, health care providers are encouraged to enroll patients currently taking Amevive® who become pregnant into the Astellas Pharma US, Inc. Pregnancy Registry by calling 1-866-834-7223.

There are no adequate and well-controlled studies of Amevive® in pregnant women. Amevive® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Reproductive toxicology studies have been performed in cynomolgus monkeys at doses up to 5 mg/kg/week (about

62 times the human dose based on body weight) and have revealed no evidence of impaired fertility or harm to the fetus due to Amevive®. No abortifacient or teratogenic effects were observed in cynomolgus monkeys following intravenous bolus injections of Amevive® administered weekly during the period of organogenesis to gestation. Amevive® underwent trans-placental passage and produced in utero exposure in the developing monkeys. In utero, serum levels of exposure in these monkeys were 23% of maternal serum levels. No evidence of fetal toxicity including adverse effects on immune system development was observed in any of these animals.

Nursing Mothers

It is not known whether Amevive® is excreted in human milk. Because many drugs are excreted in human milk, and because there exists the potential for serious adverse reactions in nursing infants from Amevive®, a decision should be made whether to discontinue nursing while taking the drug or to discontinue the use of the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Amevive® in pediatric patients have not been studied. Amevive® is not indicated for pediatric patients.

Geriatric Use

Of the 1869 patients who received Amevive® in clinical trials, a total of 129 patients were ≥ 65 years of age and 16 patients were ≥ 75 years of age. No differences in safety or efficacy were observed between older and younger patients, but there were not sufficient data to exclude important differences. Because the incidence of infections and certain malignancies is higher in the elderly population, in general, caution should be used in treating the elderly.

Overdosage

The highest dose tested in humans (0.75 mg/kg intravenous) was associated with chills, headache, arthralgia, and sinusitis within one day of dosing. Patients who have been inadvertently administered an excess of the recommended dose should be closely monitored for effects on total lymphocyte count and CD4+ T lymphocyte count.

Amevive Description

Amevive® (alefacept) is a CD2-directed LFA-3/Fc fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH2 and CH3 domains) portion of human IgG1. Alefacept is produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) mammalian cell expression system. The molecular weight of alefacept is 91.4 kilodaltons.

Amevive® is supplied as a sterile, white-to-off-white, preservative-free, lyophilized powder for intramuscular administration. After reconstitution with 0.6 mL of the supplied Sterile Water for Injection, USP, the solution of Amevive® is clear, with a pH of approximately 6.9.

Amevive® for intramuscular injection contains alefacept (15 mg), citric acid monohydrate (0.06 mg), glycine (5 mg), sodium citrate dehydrate (3.6 mg), and sucrose (12.5 mg) per 0.5 mL of reconstituted solution.

Amevive - Clinical Pharmacology

Mechanism of Action

Amevive® interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting the interaction between CD2 and its ligand, LFA-3. Activation of T lymphocytes involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in the pathophysiology of chronic plaque psoriasis.

Amevive® also causes a reduction in subsets of CD2+ T lymphocytes and circulating total CD4+ and CD8+ T lymphocyte counts. In clinical studies of Amevive®, minor changes in the numbers of circulating cells other than T lymphocytes have been observed.

Pharmacodynamics

At doses tested in clinical trials, Amevive® therapy resulted in a dose-dependent decrease in circulating total lymphocytes. This reduction predominantly affected the memory effector subset of the CD4+ and CD8+ T lymphocyte compartments (CD4+CD45RO+ and CD8+CD45RO+), the predominant phenotype in psoriatic lesions. Circulating naïve T lymphocyte and natural killer cell counts appeared to be only minimally susceptible to Amevive® treatment, while circulating B lymphocyte counts appeared not to be affected by Amevive® [see Adverse Reactions (6.1)].

Pharmacokinetics

In patients with moderate to severe plaque psoriasis, following a 7.5 mg intravenous administration, the mean volume of distribution of alefacept was 94 mL/kg, the mean clearance was 0.25 mL/h/kg, and the mean elimination half-life was approximately 270 hours. Following an intramuscular injection, bioavailability was 63%.

The pharmacokinetics of alefacept in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alefacept have not been studied.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a chronic toxicity study, cynomolgus monkeys were dosed weekly for 52 weeks with intravenous alefacept at 1 mg/kg/dose or 20 mg/kg/dose. One animal in the high dose group developed a B-cell lymphoma that was detected after 28 weeks of dosing. Additional animals in both dose groups developed B-cell hyperplasia of the spleen and lymph nodes. One-year post-treatment there was no evidence of alefacept-related lymphoma or B-cell hyperplasia in any of the remaining treated monkeys.

All animals in the study were positive for an endemic primate gammaherpes virus also known as lymphocryptovirus (LCV). Latent LCV infection is generally asymptomatic, but can lead to B-cell lymphomas when animals are immune suppressed.

In a separate study, baboons given 3 doses of alefacept at 1 mg/kg every 8 weeks were found to have centroblast proliferation in B-cell dependent areas in the germinal centers of the spleen following a 116-day washout period.

The role of Amevive® in the development of the lymphoid malignancy and the hyperplasia observed in non-human primates and the relevance to humans is unknown. Immunodeficiency-associated lymphocyte disorders (plasmacytic hyperplasia, polymorphic proliferation, and B-cell lymphomas) occur in patients who have congenital or acquired immunodeficiencies including those resulting from immunosuppressive therapy.

No formal carcinogenicity or fertility studies were conducted.

Mutagenicity studies were conducted in vitro and in vivo; no evidence of mutagenicity was observed.

Clinical Studies

Amevive® was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic (>1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic therapy or phototherapy. Each course consisted of once-weekly administration for 12 weeks (intravenous for Study 1, intramuscular for Study 2) of placebo or Amevive®. Patients could receive concomitant low potency topical steroids. Concomitant phototherapy or systemic therapy was not allowed.

In Study 1, patients were randomized to receive one or two courses of Amevive® 7.5 mg administered by intravenous bolus. The first and second courses in the two-course cohort were separated by at least a 12-week post-dosing interval. A total of 553 patients were randomized into three cohorts (Table 1).

Table 1. Treatment Group and Number of Patients Dosed in Study 1

	Course 1 (No. of patients)	Course 2 (No. of patients)
Cohort 1	Amevive® (183)	Amevive® (154)
Cohort 2	Amevive® (184)	Placebo (142)
Cohort 3	Placebo (186)	Amevive® (153)

Study 2 provided a basis for comparison of patients treated with either 10 mg or 15 mg Amevive® intramuscular. One hundred seventy-three patients were randomized to receive 10 mg of Amevive® intramuscular, 166 to receive 15 mg of Amevive® intramuscular, and 168 to receive placebo.

In Studies 1 and 2, 77% of patients had previously received systemic therapy and/or phototherapy for psoriasis. Of these, 23% and 19%, respectively, had failed to respond to at least one of these previous therapies.

Table 2 shows the treatment response in the first course of Study 1 and Study 2. Response to treatment in both studies was defined as the proportion of patients with a reduction in score on the Psoriasis Area and Severity Index (PASI)  of at least 75% from baseline at two weeks following the 12-week treatment period.

Other treatment responses included the proportion of patients who achieved a scoring of “almost clear” or “clear” by Physician Global Assessment (PGA) and the proportion of patients with a reduction in PASI of at least 50% from baseline two weeks after the 12-week treatment period.

Table 2. Percentage of Patients Responding to the First Course of Treatment in Study 1 (the Intravenous Study) and Study 2 (the Intramuscular Study) Two Weeks Post Dosing

* Cohorts 1 and 2 are combined.
	Study 1			Study 2
Treatment response: (reduction in disease activity from baseline)	Placebo (N=186)	Amevive® 7.5 mg intravenous (N=367)*	Difference (95% CI)	Placebo (N=168)	Amevive® 15 mg intramuscular (N=166)	Difference (95% CI)
≥75% reduction PASI	4%	14%	10 (6, 15)	5%	21%	16 (9, 23)
≥50% reduction PASI	10%	38%	28 (22, 35)	18%	42%	24 (14, 33)
PGA “almost clear” or “clear”	4%	11%	7 (3, 12)	5%	14%	9 (3, 15)

In Study 2, the proportion of responders to the 10 mg intramuscular dose was higher than placebo, but the difference was not statistically significant.

In both studies, onset of response to Amevive® treatment (at least a 50% reduction of baseline PASI) began 60 days after the start of therapy.

With one course of therapy in Study 1 (intravenous route), the median duration of response (defined as maintenance of a 75% or greater reduction in PASI) was 3.5 months for Amevive®-treated patients and 1 month for placebo-treated patients. In Study 2 (intramuscular route), the median duration of response was approximately 2 months for both Amevive®-treated patients and placebo-treated patients.

Most patients who had responded to either Amevive® or placebo maintained a 50% or greater reduction in PASI through the 3-month observation period.

Among responders in Study 1 who received Amevive® 7.5 mg intravenous or in Study 2 who received Amevive® 15 mg intramuscular and were followed off active treatment before Amevive® retreatment, a 50% or greater reduction in PASI was maintained for a median of 7 months.

Some patients achieved their maximal response beyond 2 weeks post-dosing. In Studies 1 and 2, an additional 11% (42/367) and 7% (12/166) of patients treated with Amevive®, respectively, achieved a 75% reduction from baseline PASI score at one or more visits after the first 2 weeks of the follow-up period.

Retreatment

Patients in Study 1 who had completed the first intravenous treatment course were eligible to receive a second treatment course if their psoriasis was less than “clear” by PGA and their CD4+ T lymphocyte count was above the lower limit of normal. The level of response (decrease in median PASI score) over the two courses of intravenous treatment is shown in Figure 1. The median reduction in PASI score was greater in patients who received a second course of Amevive® treatment (see Cohort 1) compared to patients who received placebo (see Cohort 2).

Figure 1. Median PASI Score Over Time

How Supplied/Storage and Handling

Amevive® (alefacept) is a sterile, white to off-white, preservative-free lyophilizate (15 mg/vial) for intramuscular administration provided in single-use glass vials with a bromobutyl rubber stopper and an aluminum overseal. Each vial contains 15 mg of alefacept.

Amevive® is available as follows:

Carton Contents	NDC
One- 5 mg single-use Amevive® vial One - 10 mL single-use diluent vial of Sterile Water for Injection, USP One- 1 mL syringe Two- 23 gauge 1 ¼ inch needles	0469-0021-04
Four -15 mg single-use Amevive® vials Four -10 mL single-use diluent vials of Sterile Water for Injection, USP Four- 1 mL syringes Eight- 23 gauge 1 ¼ inch needles	0469-0021-03

Store Amevive® refrigerated between 2-8°C (36-46°F). Do not freeze. Store in carton until use to protect from light.

Patient Counseling Information

Inform patients of the need for regular monitoring of white blood cell (lymphocyte) counts during therapy with Amevive®. Inform patients that the reduction in lymphocytes could increase their chances of developing an infection or a malignancy. Advise patients to inform their physician promptly if they develop any signs of an infection or malignancy while undergoing a course of treatment with Amevive®.

Advise female patients to notify their physicians if they become pregnant while taking Amevive® or within 8 weeks of discontinuing Amevive®. Inform patients that a Pregnancy Registry is available and encourage patients to enroll in the Pregnancy Registry by calling 1-866-834-7223 [see Use in Specific Populations (8.1)].

Inform patients that serious liver injury has been reported in patients receiving Amevive®. Patients should be advised to report to their physician persistent nausea, anorexia, fatigue, vomiting, abdominal pain, jaundice, easy bruising, dark urine or pale stools.

Amevive® (alefacept)

Manufactured by:

Astellas Pharma US, Inc.

Deerfield, IL 60015

US License # 1748

11C015-AMV

PRINCIPAL DISPLAY PANEL

Four Dose Pack Carton

PRINCIPAL DISPLAY PANEL

Single Dose Pack Carton

Amevive  alefacept  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0469-0021

Packaging # NDC Package Description Multilevel Packaging 1 0469-0021-04 1  In 1 CARTON None 2 0469-0021-03 4  In 1 CARTON contains a KIT 2 1  In 1 KIT This package is contained within the CARTON (0469-0021-03)

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 VIAL   0.6 mL Part 2 1 VIAL   10 mL

Part 1 of 2 Amevive  alefacept  injection, powder, lyophilized, for solution

Product Information       Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALEFACEPT (ALEFACEPT) ALEFACEPT 15 mg  in 0.5 mL

Inactive Ingredients Ingredient Name Strength CITRIC ACID MONOHYDRATE   GLYCINE   SODIUM CITRATE   SUCROSE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0.5 mL In 1 VIAL None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125036 01/30/2003

Part 2 of 2 DILUENT  water  liquid

Product Information       Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength No Active Ingredients Found

Inactive Ingredients Ingredient Name Strength WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL None

Marketing Informat

Interferon Alfa-2b Humano Recombinante

Interferon Alfa-2b Humano Recombinante may be available in the countries listed below.

Ingredient matches for Interferon Alfa-2b Humano Recombinante

Interferon alfa

Interferon alfa Interferon alfa-2b (Arg-23; His-34) (a derivative of Interferon alfa) is reported as an ingredient of Interferon Alfa-2b Humano Recombinante in the following countries:

• Chile

International Drug Name Search

Fludara

Generic Name: fludarabine (Intravenous route)

floo-DAYR-a-been

Intravenous route(Powder for Solution;Solution)

Can severely suppress bone marrow function and when used at high doses in dose-ranging studies in patients with acute leukemia, was associated with severe neurologic effects, including blindness, coma, and death. Life-threatening and sometimes fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evan's syndrome, and acquired hemophilia has been reported to occur after one or more cycles of treatment. Closely monitor patients for hemolysis. In a clinical investigation using fludarabine for injection in combination with pentostatin (deoxycoformycin) for the treatment of refractory CLL, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine for injection in combination with pentostatin is not recommended .

Commonly used brand name(s)

In the U.S.

• Fludara

Available Dosage Forms:

• Solution


• Powder for Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antimetabolite

Uses For Fludara

Fludarabine injection belongs to the group of medicines called antimetabolites. It is used to treat a type of cancer of the white blood cells called B-cell chronic lymphocytic leukemia (CLL). This medicine is used in patients with CLL who have already been treated with an alkylating agent (e.g., bendamustine) that did not work well. .

Fludarabine injection interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by fludarabine injection, other effects may also occur. Some of these may be serious and must be reported to your doctor. Other effects may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with fludarabine injection, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Fludarabine injection is to be administered only by or under the immediate supervision of your doctor.

Before Using Fludara

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of fludarabine injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

No information is available on the relationship of age to the effects of fludarabine injection in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Rotavirus Vaccine, Live

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine Type 4, Live


• Adenovirus Vaccine Type 7, Live


• Bacillus of Calmette and Guerin Vaccine, Live


• Influenza Virus Vaccine, Live


• Measles Virus Vaccine, Live


• Mumps Virus Vaccine, Live


• Pentostatin


• Rotavirus Vaccine, Live


• Rubella Virus Vaccine, Live


• Smallpox Vaccine


• Typhoid Vaccine


• Varicella Virus Vaccine


• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow problems (e.g., anemia, neutropenia, or thrombocytopenia)—Fludarabine injection may worsen these conditions.

• Chickenpox (including recent exposure) or


• Herpes zoster (shingles)—Risk of severe disease affecting other parts of the body.

• Gout (history of) or


• Kidney stones (history of)—Fludarabine may increase levels of uric acid in the body, which can cause gout or kidney stones.

• Infection—Fludarabine injection may decrease your body's ability to fight infection.

• Kidney disease—Use with caution. Effects of fludarabine injection may be increased because of slower removal of the medicine from the body.

• Transfusions—Non-irradiated blood transfusion may increase the risk of side effects of fludarabine injection.

Proper Use of Fludara

This medicine may cause nausea and vomiting. However, it is very important that you continue to receive the medicine even if you begin to feel ill. Ask your doctor for ways to lessen these effects.

You will receive this medicine while you are in a hospital or cancer treatment center. A nurse or other trained health professional will give you this medicine.

This medicine is given through a needle placed in one of your veins. It is usually given every day for 5 days. This 5-day treatment is given again every 28 days until your body responds to the medicine. Each treatment usually takes about 30 minutes.

Precautions While Using Fludara

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

While you are being treated with fludarabine injection, and after you stop treatment with it, do not have any immunizations (vaccinations) without your doctor's approval. Fludarabine injection may lower your body's resistance and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not take oral polio vaccine since there is a chance they could pass the polio virus on to you. Also, avoid persons who have recently taken oral polio vaccine. Do not get close to them and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and mouth.

Fludarabine injection can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection (e.g. pneumonia). It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you have fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination; shortness of breath; or unusual bleeding or bruising.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

You should not use this medicine if you are also taking pentostatin (Nipent®). Taking it together with this medicine may increase the chance of serious side effect.

This medicine may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount; joint pain, stiffness, or swelling; lower back, side, or stomach pain; a rapid weight gain; swelling of the feet or lower legs; or unusual tiredness or weakness.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. You should not become pregnant while you are taking this medicine and for 6 months after stopping it. If you think you have become pregnant while using the medicine, tell your doctor right away.

This medicine may cause unusual weakness, trouble in thinking, or trouble in seeing clearly. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

Fludara Side Effects

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.

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

More common

• Arm, back, or jaw pain


• black, tarry stools


• blood in the urine or stools


• chest pain or discomfort


• chest tightness or heaviness


• constipation


• cough or hoarseness


• coughing or spitting up blood


• fast or irregular heartbeat


• fever or chills


• general feeling of discomfort or illness


• lower back or side pain


• nausea


• pain


• painful, burning, or difficult urination


• pale skin


• pinpoint red spots on the skin


• shortness of breath


• sneezing


• sore throat


• sores, ulcers, or white spots on the lips or in the mouth


• stomach pain, severe


• sweating


• swelling


• tender, swollen glands in the neck


• thickening of bronchial secretions


• troubled breathing


• unusual bleeding or bruising


• unusual tiredness or weakness


• vomiting of blood or material that looks like coffee grounds


• wheezing

Less common

• Agitation


• aneurysm


• bleeding gums


• blurred vision


• confusion


• decreased urine output


• difficulty in breathing or swallowing


• dilated neck veins


• dizziness


• extreme fatigue


• fainting


• fast, pounding, or irregular heartbeat or pulse


• headache


• increased menstrual flow or vaginal bleeding


• irregular breathing


• loss of hearing


• nosebleeds


• numbness or tingling in the fingers, toes, or face


• pain, redness, or swelling in the arm or leg


• paralysis


• prolonged bleeding from cuts


• seizures


• slurred speech


• sudden and severe inability to speak


• temporary blindness


• weakness in the arm or leg on one side of the body, sudden and severe


• weight gain

Rare

• Blindness


• continuing vomiting


• dark-colored urine


• drowsiness


• frequent urination


• hives


• itching


• light-colored stools


• loss of appetite


• loss of consciousness


• lower abdominal cramping


• muscle tremors


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• rapid, deep breathing


• restlessness


• skin rash


• stomach pain


• trouble speaking, thinking, or walking


• yellow eyes or skin

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:

More common

• Abdominal pain


• bladder pain


• body aches or pain


• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings


• cloudy urine


• congestion


• diarrhea


• difficulty in moving


• dry mouth or throat


• flushed, dry skin


• frequent urge to urinate


• fruit-like breath odor


• increased hunger


• increased thirst


• increased urination


• joint pain


• muscle aching or cramping


• muscle pains or stiffness


• runny nose


• swollen joints


• trouble in swallowing


• voice changes


• weight loss

Less common

• Abdominal fullness


• bluish color of skin


• changes in skin color


• cracked lips


• dandruff


• decrease in height


• decreased urination


• difficulty in sleeping


• discouragement


• feeling sad or empty


• gaseous abdominal pain


• heartburn


• irritability


• loss of interest or pleasure


• lightheadedness


• oily skin


• pain or tenderness around the eyes and cheekbones


• rapid breathing


• recurrent fever


• stuffy nose


• sunken eye


• trouble concentrating


• wrinkled skin

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.

See also: Fludara side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Fludara resources

• Fludara Side Effects (in more detail)
• Fludara Use in Pregnancy & Breastfeeding
• Fludara Drug Interactions
• Fludara Support Group
• 1 Review for Fludara - Add your own review/rating

• Fludara Prescribing Information (FDA)


• Fludara Monograph (AHFS DI)


• Fludara MedFacts Consumer Leaflet (Wolters Kluwer)


• Fludarabine Prescribing Information (FDA)


• Oforta Prescribing Information (FDA)


• Oforta MedFacts Consumer Leaflet (Wolters Kluwer)


• Oforta Consumer Overview

Compare Fludara with other medications

• Cancer
• Chronic Lymphocytic Leukemia
• Chronic Myelogenous Leukemia
• Leukemia
• Non-Hodgkin's Lymphoma
• Stem Cell Transplant Conditioning

NORMACOL Plus Granules

NORMACOL Plus Granules

62% w/w Sterculia and 8% w/w Frangula

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription but you still need to take NORMACOL Plus carefully to get the best results from it.

• Keep this leaflet. You may need to read it again.


• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve after 4 days.


• If any of the side effects become serious, or you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

If you need the information on this leaflet in an alternative format, such as large text, or Braille please ring from the UK: 0800 198 5000.

In this leaflet:

• 1. What NORMACOL Plus is and what it is used for


• 2. Before you take NORMACOL Plus


• 3. How to take NORMACOL Plus


• 4. Possible side effects


• 5. How to store NORMACOL Plus


• 6. Further information

What NORMACOL Plus is and what it is used for

NORMACOL Plus granules contain 62% w/w sterculia and 8% w/w frangula. Sterculia is a vegetable gum from the karaya tree and frangula comes from the alder buckthorn plant. It is these natural products in NORMACOL Plus which help to relieve constipation and help keep you regular.

NORMACOL Plus is also used by people who have recently had rectal surgery or surgery to remove piles.

Before you take NORMACOL Plus

Do not take NORMACOL Plus if your doctor has told you that you have:

• A blockage in your intestine (gut)


• Total loss of muscle tone in the colon


• Faecal impaction.


• Allergy to any of the ingredients

Talk to your doctor before taking NORMACOL if:

• You are pregnant or thinking about becoming pregnant


• You are breast-feeding


• You have ulcerative colitis (an inflammatory disease of the bowel which can cause abdominal pain and bloody diarrhoea)

As with all laxatives, NORMACOL Plus should not be taken every day for long periods. If you need laxatives every day, you should see your doctor.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Taking other medicines:

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking NORMACOL Plus with food and drink

NORMACOL Plus should be taken after meals, always drink plenty of water or soft drinks.

Pregnancy and breast-feeding

Do not take NORMACOL Plus if you are pregnant or breastfeeding unless your doctor has told you to do so.

Driving and using machines

NORMACOL Plus should not affect your ability to drive or use machines.

Important information about some of the ingredients of NORMACOL Plus

This medicine contains 1.25-2.5 mmol sodium per dose. This should be taken into consideration by patients on a controlled sodium (low salt) diet.

How to take NORMACOL Plus

Always take NORMACOL Plus exactly as instructed. You should check with your doctor or pharmacist if you are not sure.

• The usual dose for adults and the elderly is 1 to 2 sachets, or 1 to 2 heaped 5ml spoonfuls, taken once or twice a day after meals. Do not take NORMACOL Plus if you are lying down or just before you go to bed.


• NORMACOL Plus can be used in children aged between 6 to 12 years but only as directed by a doctor.

If NORMACOL Plus does not work after you have taken it for 4 days, do not take anymore, and see your doctor or pharmacist.

• 
  To take NORMACOL Plus, put the dry granules on your tongue from the sachet, spoon or your hand, or just take a few at a time if that is easier.


• Alternatively you can sprinkle NORMACOL Plus onto soft food such as yoghurt.


• Swallow the granules with plenty of water or a cool drink, so that the oesophagus (gullet) does not become blocked. Never chew or crush the granules.

If you take more NORMACOL Plus than you should and do not have bowel movements, see your doctor.

If you forget to take NORMACOL Plus, just take the next normal dose at the usual time. Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible side effects

Like all medicines, NORMACOL Plus can cause side effects, although not everybody gets them:

• The bowel may become blocked and some people may experience stomach cramps.


• Occasionally NORMACOL Plus causes a swollen stomach.


• The oesophagus (gullet) can become blocked if NORMACOL Plus is not taken with enough fluid, or too much NORMACOL Plus is taken.


• Some people may have an allergic reaction which may include an itchy skin, rash, or difficulty in breathing.

If any of the side effects become serious, or you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store NORMACOL Plus

Keep all medicines out of the reach and sight of children.

Store in a dry place below 25°C.

Do not use NORMACOL Plus after the expiry date which is stated on the sachet/carton as month/year. The expiry date refers to the last day of the month.

Further information

What NORMACOL Plus contains

The active substances are sterculia and frangula. The granules contain 62% w/w sterculia and 8% w/w frangula.

The other ingredients are sodium bicarbonate, sucrose, talc, paraffin wax, peppermint flavour and the colours E110, E127 and E132.

What NORMACOL Plus looks like and contents of the pack

Each carton contains 200 or 500 grams of brown granules, or if it is a sachet pack, 60 sachets each containing 7 grams of granules.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is

Norgine Ltd

Moorhall Road

Harefield

Middlesex

UB9 6NS

UK

It is made by

Norgine Ltd

Hengoed

Mid Glamorgan

CF82 8SJ

UK

UK Marketing Authorisation Number: PL 00322/5011R

The leaflet was last approved in February 2009

NORMACOL is a registered trademark.

Legal Category: GSL

Minims Oxybuprocaine Hydrochloride 0.4%

Minims*

Oxybuprocaine Hydrochloride 0.4% w/v

Oxybuprocaine hydrochloride

About Minims Oxybuprocaine Hydrochloride

The name of this medicine is Minims Oxybuprocaine Hydrochloride. Each Minims unit contains 0.4% w/v oxybuprocaine hydrochloride solution.

The active ingredient in this medicine is oxybuprocaine hydrochloride. This is the new name for benoxinate hydrochloride. The ingredient itself has not changed.

It also contains purified water and a small amount of hydrochloric acid. Each Minims unit is a sterile single use eyedrop containing approximately 0.5ml of solution. Each carton contains 20 Minims units. Oxybuprocaine hydrochloride is used as a local anaesthetic.

Who makes this medicine ?

Minims Oxybuprocaine Hydrochloride 0.4% w/v are manufactured by

Laboratoire Chauvin

Z.I. Ripotier

07200/Aubenas

France

The Marketing Authorisations for Minims Oxybuprocaine Hydrochloride 0.4% (PL 0033/5004R & PA 118/9/1) are held by

Chauvin Pharmaceuticals Ltd.

106 London Road

Kingston-Upon-Thames

KT2 6TN

England

What is it for ?

This medicine is used to numb the eye temporarily. This could be necessary for a number of reasons. Most often, this medicine is used to allow your doctor or eye specialist to measure the pressure inside your eye, fit contact lenses or perform minor operations.

Before using this medicine

This product should not be used in patients who are allergic to oxybuprocaine. Make sure that you tell your doctor or eye specialist if you have had an allergic reaction to oxybuprocaine in the past.

When your eye has been numbed it is important to keep it free of dust and bacteria. Your doctor or eye specialist will make sure that your eye is properly protected.

If you are pregnant (or if you think that you might be pregnant) you should tell your doctor or eye specialist before this medicine is used. It is possible that you will still receive it, but it is also possible that an alternative may be used.

Oxybuprocaine is more comfortable for your eyes than some local anaesthetics but you may still feel some stinging when the drops are first added. Your sight may also become blurred. Make sure that you do not try to drive or use machinery until you sight has returned to normal.

Local anaesthetic eye drops can damage the surface of the eye if they are used too much or too often. Your doctor or eye specialist will make sure that this does not happen. One drop of solution is enough to allow your doctor or eye specialist to measure the pressure inside your eye.

Two drops, one and a half minutes apart is enough to allow contact lenses to be fitted.

Three drops at one and a half minute intervals is enough to allow minor operations to be performed.

The doctor or eye specialist will put the drops in your eye for you. You may be asked to press on the inner corners of your eyes for a minute to prevent the solution draining into your nose and throat. The Minims unit should then be discarded. Your eye will remain numb for about one hour, depending on how many drops you received.

It is very unlikely that you will suffer an overdose from this medicine, but if you suddenly feel unwell after receiving the drops, tell your doctor or eye specialist.

After using this medicine

This medicine is not expected to cause you any unwanted side effects, but you should tell your doctor or pharmacist if you are worried about anything.

Storing this medicine

• The expiry date is printed on each Minims unit overwrap and on the carton label. Do not use it after this date.


• This medicine should be stored below 25°C and protected from light. Do not allow to freeze.

This leaflet applies only to Minims Oxybuprocaine Hydrochloride 0.4% w/v, but it does not contain all the information known about it.

If you have any questions or are not sure about anything, ask a doctor, eye specialist or pharmacist.

Date of (Partial) Revision of Text : May 2005.

* Trade Mark

Chauvin Pharmaceuticals Ltd.

106 London Road

Kingston-Upon-Thames

KT2 6TN

England

Tel :020 8781 2900

Fax :020 8781 2901

Art. 76424 0504120/3

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