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

Félodipine Winthrop

Félodipine Winthrop may be available in the countries listed below.

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Felodipine

Felodipine is reported as an ingredient of Félodipine Winthrop in the following countries:

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Chirocaine 2.5mg / ml & 5.0mg / ml solution for injection / concentrate for solution for infusion

Chirocaine

2.5mg/ml and 5.0mg/ml solution for injection/concentrate for solution for infusion

Levobupivacaine

Read all of this leaflet carefully before you start taking this medicine

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


• If you have any further questions, please ask your doctor or nurse.


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

In this leaflet:

1. What Chirocaine is and what it is used for

2. Before you are given Chirocaine

3. How you will be given Chirocaine

4. Possible side effects

5. How to store Chirocaine

6. Further information

What Chirocaine Is And What It Is Used For

Chirocaine belongs to a group of medicines called local anaesthetics. This type of medicine is used to make an area of the body numb or free from pain.

In adults:

Chirocaine is used as a local anaesthetic to numb parts of the body before major surgery (for example as an epidural for caesarean section) and minor surgery (such as on the eye and mouth).

It is also used for pain relief

• after major surgery


• during childbirth

In children:

Chirocaine can also be used with children to numb parts of the body before surgery and for pain relief after minor surgery, such as the repair of a groin hernia.

Before You Are Given Chirocaine

Do not use Chirocaine:

• if you are allergic (hypersensitive) to levobupivacaine, to any similar local anaesthetics or to any of the other ingredients in Chirocaine (see Section 6)


• if you have very low blood pressure


• as a type of pain relief given by injection into the area around the neck of the womb (the cervix) during the early stage of labour (paracervical block)


• to numb an area by injecting Chirocaine into a vein

Take special care with Chirocaine:

Tell your doctor before you are given Chirocaine if you have any of the diseases or conditions below. You may need to be checked more closely or given a smaller dose.

• if you have a heart condition


• if you suffer from diseases of the nervous system


• if you are weak or ill


• if you are elderly


• if you have liver disease.

Taking other medicines

Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines you have obtained without a prescription. In particular, tell them if you are taking medicines for:

• irregular heart beats (such as mexiletine)


• fungal infections (such as ketoconazole) since this may affect how long Chirocaine stays in your body


• asthma (such as theophylline) since this may affect how long Chirocaine stays in your body.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding.

Chirocaine must not be a given for pain relief by injection into the area around the neck of the womb or cervix during childbirth (paracervical block).

The effect of Chirocaine on the child during the early stages of pregnancy is not known. Therefore, Chirocaine should not be used during the first three months of your pregnancy, unless your doctor thinks it is necessary.

It is not known if levobupivacaine passes into breast milk. However from the experience with a similar drug, only small amounts of levobupivacaine are expected to pass into breast milk. Breast-feeding is therefore possible after having a local anaesthesic.

Driving and using machines

The use of Chirocaine can have a considerable effect on the ability to drive or use machines. You must not drive or operate machinery until all the effects of Chirocaine and the immediate effects of surgery have worn off. Make sure you get advice about this matter from the doctor or nurse who is treating you, before leaving hospital.

Important information about some of the ingredients of Chirocaine

This medicinal product contains 3.6 mg/mL sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

How You Will Be Given Chirocaine

Your doctor will give you Chirocaine by injection through a needle or into a small tube in your back (epidural). Chirocaine can also be injected into other parts of the body to numb the area that you will have treated, such as the eye, arm or leg.

Your doctor and nurse will watch you carefully while you are being given Chirocaine.

Dosage

The amount of Chirocaine you will be given and how often it is given will depend on why it is being used and also on your health, age and weight. The smallest dose that can produce numbness in the required area will be used. The dose will be carefully worked out by your doctor.

When Chirocaine is used for pain relief during labour or for childbirth by caesarean section (an epidural), the dose used should be particularly carefully controlled.

If you get more Chirocaine than you should

If you get more Chirocaine than you should, you may have numbness of the tongue, dizziness, blurred vision, muscle twitching, severe breathing difficulties (including stopping breathing) and even fits (convulsions). If you notice any of these symptoms, tell your doctor immediately. Sometimes too much Chirocaine may also cause low blood pressure, fast or slow heartbeats and changes in your heart rhythm. Your doctor may need to give you other medicines to help stop these symptoms.

Possible Side Effects

Like all medicines, Chirocaine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately if you notice any of the following side effects. Some side effects with Chirocaine can be serious.

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

rare: affects 1 to 10 users in 10,000

very rare: affects less than 1 user in 10,000

not known: frequency cannot be estimated from the available data

Very common side effects are:

• feeling tired or weak, short of breath, looking pale (these are all signs of anaemia)


• low blood pressure


• nausea

Common side effects are:

• dizziness


• headache


• vomiting


• problems (distress) for an unborn child


• back pain


• high body temperature (fever)


• pain after surgery

Other side effects (frequently not known) are:

• serious allergic (hypersensitive) reactions which cause severe breathing difficulties, difficulty in swallowing, hives and very low blood pressure.


• allergic (hypersensitive) reactions recognised by red itchy skin, sneezing, sweating a lot, rapid heartbeat, fainting or swelling of the face, lips, mouth, tongue or throat.


• fits (convulsions)


• loss of consciousness


• drowsiness


• blurred vision


• breathing stopping


• localized tingling


• numbness of the tongue


• muscle weakness or twitching


• loss of bladder or bowel control


• paralysis

Fast, slow or irregular heartbeats, and heart rhythm changes that can be seen on an ECG, have also been reported as side effects.

Rarely, some side effects may be permanent.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse right away.

How To Store Chirocaine

• Keep out of the reach and sight of children.


• Do not use Chirocaine after the expiry date which is stated on the label. The expiry date refers to the last day of that month.


• Your doctor will store this medicine for you.


• The solution should be used immediately after opening


• The solution should not be used if there are visible particles in it.

Medicines should not be disposed of through wastewater or household waste. These measures will help to protect the environment.

Further Information

What Chirocaine contains

The active ingredient is levobupivacaine (as hydrochloride).

Chirocaine 2.5 mg/ml solution for injection/concentrate for solution for infusion: One ml contains 2.5 mg levobupivacaine (as hydrochloride). Each ampoule contains 25 mg in 10 ml.

Chirocaine 5 mg/ml solution for injection/concentrate for solution for infusion: One ml contains 5 mg levobupivacaine (as hydrochloride). Each ampoule contains 50 mg in 10 ml.

The other ingredients are water for injection, sodium chloride, sodium hydroxide and a small quantity of hydrochloric acid.

What Chirocaine looks like and contents of the pack

Chirocaine Solution for injection / concentrate for solution for infusion is available in strengths containing 2.5 mg or 5.0 mg of levobupivacaine per ml. It is a clear, colourless solution, in polypropylene ampoules. Each ampoule contains 25 mg or 50 mg levobupivacaine in a 10 ml ampoule. It is supplied in packs of 5, 10 or 20 ampoules.

Marketing Authorisation Holder

In the UK:

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

Manufacturer

Abbott S.r.l.

Campoverde Di Aprilia

04010 Latina

Italy

This medicinal product is authorised in the Member States of the EEA under the following names:

Chirocaine: Sweden, Portugal, Switzerland, Latvia, Netherlands, Poland, France, UK, Ireland, Finland, Greece, Slovenia, Austria, Belgium, Hungary, Bulgaria, Czech Republic, Luxembourg

Chirocain: Germany

Chirocane: Spain

This leaflet was last approved in May 2010

131-850-04

Glucosaminoglycan Polysulfate

ATC (Anatomical Therapeutic Chemical Classification)

M01AX12

CAS registry number (Chemical Abstracts Service)

0063449-40-1

Therapeutic Category

Anti-inflammatory agent

Chemical Name

Poly[(N-acetyl-D-galactosamin, D-glucuronsäure)poly-O-hydrogensulfat]

Foreign Name

• Glycosaminoglycan polysulfat (German)

Generic Names

• GAGPS (IS)
• Glycosaminoglycan, polysulfated (IS)
• MPS (IS)
• Mucopolysaccharides, (poly)sulfated (IS)
• Sulfomucopolysaccharidum (IS)

Brand Names

• Hirudoid
  Medinova, Vietnam



• Movilat (Glucosaminoglycan Polysulfate and Salicylic Acid)
  Stada, Spain

International Drug Name Search

Glossary

IS	Inofficial Synonym

Click for further information on drug naming conventions and International Nonproprietary Names.

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• Austria


• Estonia


• Georgia


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• Latvia


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Captopril Domesco

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Captopril

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Chirocaine 2.5mg / ml solution for injection / concentrate for solution for infusion

1. Name Of The Medicinal Product

Chirocaine 2.5 mg/ml solution for injection/concentrate for solution for infusion.

2. Qualitative And Quantitative Composition

One ml contains 2.5 mg levobupivacaine as levobupivacaine hydrochloride.

Each ampoule contains 25 mg in 10 ml.

Excipients: 3.6mg/ml of sodium per ampoule.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection/concentrate for solution for infusion.

Clear colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

Surgical anaesthesia

- Major, e.g. epidural (including for caesarean section), intrathecal, peripheral nerve block.

- Minor, e.g. local infiltration, peribulbar block in ophthalmic surgery.

Pain management

- Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain especially post-operative pain or labour analgesia.

Children

Analgesia (ilioinguinal/iliohypogastric blocks).

4.2 Posology And Method Of Administration

Levobupivacaine should be administered only by, or under the supervision of, a clinician having the necessary training and experience.

The table below is a guide to dosage for the more commonly used blocks. For analgesia (e.g. epidural administration for pain management), the lower concentrations and doses are recommended. Where profound or prolonged anaesthesia is required with dense motor block (e.g. epidural or peribulbar block), the higher concentrations may be used. Careful aspiration before and during injection is recommended to prevent intravascular injection.

Aspiration should be repeated before and during administration of a bolus dose, which should be injected slowly and in incremental doses, at a rate of 7.5–30 mg/min, while closely observing the patient's vital functions and maintaining verbal contact.

If toxic symptoms occur, the injection should be stopped immediately.

Maximum dose

The maximum dosage must be determined by evaluating the size and physical status of the patient, together with the concentration of the agent and the area and route of administration. Individual variation in onset and duration of block does occur. Experience from clinical studies shows onset of sensory block adequate for surgery in 10-15 minutes following epidural administration, with a time to regression in the range of 6-9 hours.

The recommended maximum single dose is 150 mg.Where sustained motor and sensory block are required for a prolonged procedure, additional doses may be required. The maximum recommended dose during a 24 hour period is 400 mg. For post-operative pain management, the dose should not exceed 18.75 mg/hour.

Obstetrics

For caesarean section, higher concentrations than the 5.0 mg/ml solution should not be used (See section 4.3). The maximum recommended dose is 150 mg.

For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/hour.

Children

In children, the maximum recommended dose for analgesia (ilioinguinal/iliohypogastric blocks) is 1.25 mg/kg/side.

The safety and efficacy of levobupivacaine in children for other indications have not been established.

Special populations

Debilitated, elderly or acutely ill patients should be given reduced doses of levobupivacaine commensurate with their physical status.

In the management of post-operative pain, the dose given during surgery must be taken into account.

There are no relevant data in patients with hepatic impairment (see sections 4.4 and 5.2).

Table of Doses

	Concentration (mg/ml)1	Dose	Motor Block
Surgical Anaesthesia
Epidural (slow) bolus2 for surgery - Adults	5.0-7.5	10-20 ml (50-150 mg)	Moderate to complete
Epidural slow injection3 for Caesarean Section	5.0	15-30 ml (75-150 mg)	Moderate to complete
Intrathecal	5.0	3 ml (15 mg)	Moderate to complete
Peripheral Nerve Ilioinguinal/Iliohypogastric blocks in children <12 years	2.5-5.0 2.5-5.0	1-40 ml (2.5-150 mg max.) 0.25-0.5 ml/kg (0.625-2.5 mg/kg)	Moderate to complete Not applicable
Ophthalmic (peribulbar block)	7.5	5–15 ml (37.5-112.5 mg)	Moderate to complete
Local Infiltration - Adults	2.5	1-60 ml (2.5-150 mg max.)	Not applicable
Pain Management4 Labour Analgesia (epidural bolus5)	2.5	6-10 ml (15-25 mg)	Minimal to moderate
Labour Analgesia (epidural infusion)	1.256	4-10 ml/h (5-12.5 mg/h)	Minimal to moderate
Post-operative pain	1.256 2.5	10-15ml/h (12.5-18.75mg/h) 5-7.5ml/h (12.5 –18.75mg/h)	Minimal to moderate

¹ Levobupivacaine solution for injection/concentration for solution for infusion is available in 2.5, 5.0 and 7.5 mg/ml solutions.

² Spread over 5 minutes (see also text).

³ Given over 15-20 minutes.

⁴ In cases where levobupivacaine is combined with other agents e.g. opioids in pain management, the levobupivacaine dose should be reduced and use of a lower concentration (e.g. 1.25 mg/ml) is preferable.

⁵ The minimum recommended interval between intermittent injections is 15 minutes.

⁶ For information on dilution, see section 6.6.

4.3 Contraindications

General contra-indications related to regional anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Levobupivacaine solutions are contra-indicated in patients with a known hypersensitivity to levobupivacaine, local anaesthetics of the amide type or any of the excipients (see section 4.8).

Levobupivacaine solutions are contra-indicated for intravenous regional anaesthesia (Bier's block).

Levobupivacaine solutions are contra-indicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.

Levobupivacaine solutions are contra-indicated for use in paracervical block in obstetrics (see section 4.6).

4.4 Special Warnings And Precautions For Use

All forms of local and regional anaesthesia with levobupivacaine should be performed in well-equipped facilities and administered by staff trained and experienced in the required anaesthetic techniques and able to diagnose and treat any unwanted adverse effects that may occur.

Levobupivacaine can cause acute allergic reactions, cardiovascular effects and neurological damage, see section 4.8.

Levobupivacaine should be used with caution for regional anaesthesia in patients with impaired cardiovascular function e.g. serious cardiac arrhythmias.

The introduction of local anesthetics via either intrathecal or epidural administration into the central nervous system in patients with preexisting CNS diseases may potentially exacerbate some of these disease states. Therefore, clinical judgment should be exercised when contemplating epidural or intrathecal anesthesia in such patients.

This medicinal product contains 3.6 mg/ml sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

Epidural Anesthesia

During epidural administration of levobupivacaine, concentrated solutions (0.5-0.75%) should be administered in incremental doses of 3 to 5 ml with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. When a large dose is to be injected, e.g. in epidural block, a test dose of 3-5 ml lidocaine with adrenaline is recommended. An inadvertent intravascular injection may then be recognised by a temporary increase in heart rate and accidental intrathecal injection by signs of a spinal block.

Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given.

Epidural anaesthesia with any local anaesthetic may cause hypotension and bradycardia. All patients must have intravenous access established. The availability of appropriate fluids, vasopressors, anaesthetics with anticonvulsant properties, myorelaxants, and atropine, resuscitation equipment and expertise must be ensured (see section 4.9).

Major regional nerve blocks

The patient should have I.V. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Reactions may be due to intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

Use in Ophthalmic Surgery

Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anaesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions.

Special populations

Debilitated, elderly or acutely ill patients: levobupivacaine should be used with caution in debilitated, elderly or acutely ill patients (see section 4.2).

Hepatic impairment: since levobupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow e.g. alcoholics or cirrhotics (see section 5.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicate that the CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine. Although no clinical studies have been conducted, metabolism of levobupivacaine may be affected by CYP3A4 inhibitors eg: ketoconazole, and CYP1A2 inhibitors eg: methylxanthines.

Levobupivacaine should be used with caution in patients receiving anti-arrhythmic agents with local anaesthetic activity, e.g., mexiletine, or class III anti-arrhythmic agents since their toxic effects may be additive.

No clinical studies have been completed to assess levobupivacaine in combination with adrenaline.

4.6 Pregnancy And Lactation

Pregnancy

Levobupivacaine solutions are contraindicated for use in paracervical block in obstetrics. Based on experience with bupivacaine foetal bradycardia may occur following paracervical block (see section 4.3).

For levobupivacaine, there are no clinical data on first trimester-exposed pregnancies. Animal studies do not indicate teratogenic effects but have shown embryo-foetal toxicity at systemic exposure levels in the same range as those obtained in clinical use (see section 5.3). The potential risk for human is unknown. Levobupivacaine should therefore not be given during early pregnancy unless clearly necessary.

Nevertheless, to date, the clinical experience of bupivacaine for obstetrical surgery (at the term of pregnancy or for delivery) is extensive and has not shown a foetotoxic effect.

Lactation

Levobupivacaine excretion in breast milk is unknown. However, levobupivacaine is likely to be poorly transmitted in the breast milk, as for bupivacaine. Thus breast feeding is possible after local anaesthesia.

4.7 Effects On Ability To Drive And Use Machines

Levobupivacaine can have a major influence on the ability to drive or use machines. Patients should be warned not to drive or operate machinery until all the effects of the anaesthesia and the immediate effects of surgery are passed.

4.8 Undesirable Effects

The adverse drug reactions for Chirocaine are consistent with those known for its respective class of medicinal products. The most commonly reported adverse drug reactions are hypotension, nausea, anaemia, vomiting, dizziness, headache, pyrexia, procedural pain, back pain and foetal distress syndrome in obstetric use (see table below).

Adverse reactions reported either spontaneously or observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: very common (

System Organ Class	Frequency	Adverse Reaction
Blood and lymphatic system disorders	Very Common	Anaemia
Immune system disorders	Not known Not known	Allergic reactions (in serious cases anaphylactic shock) Hypersensitivity
Nervous system disorders	Common Common Not known Not known Not known Not known Not known Not known	Dizziness Headache Convulsion Loss of consciousness Somnolence Syncope Paraesthesia Paraplegia
Eye disorder	Not known	Vision blurred
Cardiac disorders	Not known Not known Not known Not known Not known	Atrioventricular block Cardiac arrest Ventricular tachyarrhythmia Tachycardia Bradycardia
Vascular disorders	Very common	Hypotension
Respiratory, thoracic and mediastinal disorders	Not known Not known Not known Not known	Respiratory arrest Laryngeal oedema Apnoea Sneezing
Gastrointestinal disorders	Very Common Common Not known	Nausea Vomiting Hypoaesthesia oral Loss of sphincter control
Skin and subcutaneous tissue disorders	Not known Not known Not known Not known Not known	Angioedema Urticaria Pruritus Hyperhidrosis Erythema
Musculoskeletal and connective tissue disorders	Common Not known Not known	Back pain Muscle twitching Muscular weakness
Renal and urinary disorders	Not known	Bladder dysfunction
Pregnancy, puerperium and perinatal conditions	Common	Foetal distress syndrome
General disorders and administration site conditions	Common	Pyrexia
Investigations	Not known Not known	Cardiac output decreased Electrocardiogram change
Injury, poisoning and procedural complications	Common	Procedural pain

Adverse reactions with local anaesthetics of the amide type are rare, but they may occur as a result of overdosage or unintentional intravascular injection and may be serious.

Cross-sensitivity among members of the amide-type local anesthetic group have been reported (see section 4.3).

Accidental intrathecal injection of local anaesthetics can lead to very high spinal anaesthesia.

Cardiovascular effects are related to depression of the conduction system of the heart and a reduction in myocardial excitability and contractility. Usually these will be preceded by major CNS toxicity, i.e. convulsions, but in rare cases, cardiac arrest may occur without prodromal CNS effects.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance or an injection of a non-sterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Rarely, these may be permanent.

4.9 Overdose

Accidental intravascular injection of local anaesthetics may cause immediate toxic reactions. In the event of overdose, peak plasma concentrations may not be reached until 2 hours after administration depending upon the injection site and, therefore, signs of toxicity may be delayed. The effects of the drug may be prolonged.

Systemic adverse reactions following overdose or accidental intravascular injection reported with long acting local anaesthetic agents involve both CNS and cardiovascular effects.

CNS Effects

Convulsions should be treated immediately with intravenous thiopentone or diazepam titrated as necessary. Thiopentone and diazepam also depress central nervous system, respiratory and cardiac function. Therefore their use may result in apnoea. Neuro-muscular blockers may be used only if the clinician is confident of maintaining a patent airway and managing a fully paralysed patient.

If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthetic on the heart, may result in cardiac arrhythmias, ventricular fibrillation or cardiac arrest.

Cardiovascular Effects

Hypotension may be prevented or attenuated by pre-treatment with a fluid load and/or the use of vasopressors. If hypotension occurs it should be treated with intravenous crystalloids or colloids and/or incremental doses of a vasopressor such as ephedrine 5-10 mg. Any coexisting causes of hypotension should be rapidly treated.

If severe bradycardia occurs, treatment with atropine 0.3-1.0 mg will normally restore the heart rate to an acceptable level.

Cardiac arrhythmia should be treated as required and ventricular fibrillation should be treated by cardioversion.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Local anaesthetics, amide

ATC Code N01B B10

Levobupivacaine is a long acting local anaesthetic and analgesic. It blocks nerve conduction in sensory and motor nerves largely by interacting with voltage sensitive sodium channels on the cell membrane, but also potassium and calcium channels are blocked. In addition, levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on the cardiovascular and central nervous systems are most important for the occurrence of clinical adverse reactions.

The dose of levobupivacaine is expressed as base, whereas, in the racemate bupivacaine the dose is expressed as hydrochloride salt. This gives rise to approximately 13% more active substance in levobupivacaine solutions compared to bupivacaine. In clinical studies at the same nominal concentrations levobupivacaine showed similar clinical effect to bupivacaine.

In a clinical pharmacology study using the ulnar nerve block model, levobupivacaine was equipotent with bupivacaine.

5.2 Pharmacokinetic Properties

In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. The plasma concentration of levobupivacaine following therapeutic administration depends on dose and, as absorption from the site of administration is affected by the vascularity of the tissue, on route of administration.

There are no relevant data in patients with hepatic impairment (see section 4.4).

There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.

Plasma protein binding of levobupivacaine in man was evaluated in vitro and was found to be> 97% at concentrations between 0.1 and 1.0 μg/ml.

In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, C_max 1.4 + 0.2 μg/ml and AUC 70 + 27 μg•min/ml.

The mean C_max and AUC(0-24h) of levobupivacaine were approximately dose-proportional following epidural administration of 75 mg (0.5%) and 112.5 mg (0.75%) and following doses of 1 mg/kg (0.25%) and 2 mg/kg (0.5%) used for brachial plexus block. Following epidural administration of 112.5 mg (0.75%) the mean C_max and AUC values were 0.58 µg/ml and 3.56µg•h/ml respectively.

The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. The volume of distribution after intravenous administration was 67 litres.

Levobupivacaine is extensively metabolised with no unchanged levobupivacaine detected in urine or faeces. 3-hydroxylevobupivacaine, a major metabolite of levobupivacaine, is excreted in the urine as glucuronic acid and sulphate ester conjugates. In vitro studies showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl-levobupivacaine and 3-hydroxylevobupivacaine respectively.These studies indicate that the metabolism of levobupivacaine and bupivacaine are similar.

Following intravenous administration, recovery of levobupivacaine was quantitative with a mean total of about 95% being recovered in urine (71%) and faeces (24%) in 48 hours.

There is no evidence of in vivo racemisation of levobupivacaine.

5.3 Preclinical Safety Data

In an embryo-foetal toxicity study in rats, an increased incidence of dilated renal pelvis, dilated ureters, olfactory ventricle dilatation and extra thoraco-lumbar ribs was observed at systemic exposure levels in the same range as those obtained at clinical use. There were no treatment-related malformations.

Levobupivacaine was not genotoxic in a standard battery of assays for mutagenicity and clastogenicity. No carcinogenicity testing has been conducted.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric acid

Water for Injections

6.2 Incompatibilities

Levobupivacaine may precipitate if diluted with alkaline solutions and should not be diluted or co-administered with sodium bicarbonate injections. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Shelf life as packaged for sale: 3 years

Shelf life after first opening: The product should be used immediately

Shelf life after dilution in sodium chloride solution 0.9%: Chemical and physical in-use stability has been demonstrated for 7 days at 20-22°C. Chemical and physical in-use stability with clonidine, morphine or fentanyl has been demonstrated for 40 hours at 20-22°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special Precautions For Storage

Polypropylene ampoules: polypropylene ampoules do not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Chirocaine is available in two presentations;

10 ml polypropylene ampoule in packs of 5, 10 & 20

10 ml polypropylene ampoule, in sterile blister packs of 5, 10 & 20

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Discard any unused solution.

The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used.

A sterile blister container should be chosen when a sterile ampoule surface is required. Ampoule surface is not sterile if sterile blister is pierced.

Dilutions of levobupivacaine standard solutions should be made with sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic techniques.

Clonidine 8.4 μg/ml, morphine 0.05 mg/ml and fentanyl 4 μg/ml have been shown to be compatible with levobupivacaine in sodium chloride 9 mg/ml (0.9%) solution for injection.

7. Marketing Authorisation Holder

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00037/0300

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 06 January 2000

Date of last renewal: 18th December 2008

10. Date Of Revision Of The Text

02^nd July 2010