Toviaz

Pronunciation: FES-oh-TER-oh-deen
Generic Name: Fesoterodine
Brand Name: Toviaz

Toviaz is used for:

Treating overactive bladder with symptoms of urinary frequency, urgency, and leakage. It may also be used for other conditions as determined by your doctor.

Toviaz is an antimuscarinic agent. It works by blocking a chemical that causes contractions of the bladder.

Do NOT use Toviaz if:

• you are allergic to any ingredient in Toviaz or to tolterodine


• you have delayed or slow emptying of your stomach (gastric retention), uncontrolled narrow-angle glaucoma, or severe liver problems, or you are unable to urinate


• you are taking a solid oral potassium product (eg, tablet)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Toviaz:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have glaucoma or increased pressure in the eye; a blockage of the bladder, stomach, or bowel; stomach or bowel problems (eg, severe constipation); liver or kidney problems; myasthenia gravis (muscle weakness); or trouble urinating


• if you or a family member has a history of irregular heartbeat (eg, prolonged QT)

Some MEDICINES MAY INTERACT with Toviaz. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticholinergics (eg, scopolamine), clarithromycin, ketoconazole, itraconazole, nefazodone, posaconazole, protease inhibitors (eg, ritonavir), or telithromycin because they may increase the risk of Toviaz's side effects


• Solid oral potassium products (eg, tablets) because the risk of stomach or bowel irritation may be increased by Toviaz

This may not be a complete list of all interactions that may occur. Ask your health care provider if Toviaz may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Toviaz:

Use Toviaz as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Toviaz. Talk to your pharmacist if you have questions about this information.


• Take Toviaz by mouth with or without food. Take it with liquid.


• Swallow Toviaz whole. Do not break, crush, or chew before swallowing.


• If you miss a dose of Toviaz, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses on the same day.

Ask your health care provider any questions you may have about how to use Toviaz.

Important safety information:

• Toviaz may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Toviaz with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• A severe and sometimes life-threatening side effect called angioedema has been reported with Toviaz. Contact your doctor at once if you develop swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness.


• Do not become overheated in hot weather or while you are being active; heat exhaustion may occur.


• Drink plenty of fluids, maintain good oral hygiene, and suck on sugarless hard candy to relieve dry mouth.


• Use Toviaz with caution in the ELDERLY; they may be more sensitive to its effects, especially an increased risk of urinary tract infection, urinary retention, dry mouth, constipation, indigestion, heartburn, or dizziness.


• Toviaz should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if Toviaz can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Toviaz while you are pregnant. It is not known if Toviaz is found in breast milk. If you are or will be breast-feeding while you use Toviaz, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Toviaz:

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

Blurred vision; constipation; dizziness; drowsiness; dry eyes; dry mouth; indigestion; stomach pain.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); chest pain; confusion; difficult or painful urination; disorientation; fast or irregular heartbeat; hallucinations; memory problems; severe dizziness; severe or persistent constipation or diarrhea; severe stomach cramps or pain; swelling of the hands, ankles, or feet.

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

See also: Toviaz side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include difficulty breathing; difficulty urinating; dilated pupils; excitation; fast heartbeat; hallucinations; seizures.

Proper storage of Toviaz:

Store Toviaz at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Toviaz out of the reach of children and away from pets.

General information:

• If you have any questions about Toviaz, please talk with your doctor, pharmacist, or other health care provider.


• Toviaz is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Toviaz. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Toviaz resources

• Toviaz Side Effects (in more detail)
• Toviaz Use in Pregnancy & Breastfeeding
• Drug Images
• Toviaz Drug Interactions
• Toviaz Support Group
• 18 Reviews for Toviaz - Add your own review/rating

• Toviaz Prescribing Information (FDA)


• Toviaz Monograph (AHFS DI)


• Toviaz Advanced Consumer (Micromedex) - Includes Dosage Information


• Toviaz Consumer Overview

Compare Toviaz with other medications

• Overactive Bladder
• Urinary Incontinence

Leukine

sargramostim

Dosage Form: liquid, injection

Rx only

Leukine Description

Leukine®  (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. Leukine is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500, 16,800 and 15,500 daltons. The amino acid sequence of Leukine differs from the natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from the native protein. Sargramostim has been selected as the proper name for yeast-derived rhu GM-CSF.

The liquid Leukine presentation is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Leukine is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP. Liquid Leukine has a pH range of 6.7 - 7.7 and lyophilized Leukine has a pH range of 7.1 - 7.7.

Liquid Leukine and reconstituted lyophilized Leukine are clear, colorless liquids suitable for subcutaneous injection (SC) or intravenous infusion (IV).

Liquid Leukine contains 500 mcg (2.8 x 106 IU/mL) sargramostim and 1.1% benzyl alcohol in a 1 mL solution. The vial of lyophilized Leukine contains 250 mcg (1.4 x 106 IU/vial) sargramostim.

The liquid Leukine vial and reconstituted lyophilized Leukine vial also contain 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, as excipients. Biological potency is expressed in International Units (IU) as tested against the WHO First International Reference Standard. The specific activity of Leukine is approximately 5.6 x 106 IU/mg.

Leukine - Clinical Pharmacology

General

GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.

GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors.1 However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2

In vitro Studies of Leukine in Human Cells

The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of Leukine. In vitro exposure of human bone marrow cells to Leukine at concentrations ranging from 1–100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocytemacrophage colonies.3 Chemotactic, anti-fungal and anti-parasitic4 activities of granulocytes and monocytes are increased by exposure to Leukine in vitro. Leukine increases the cytotoxicity of monocytes toward certain neoplastic cell lines3 and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.

In vivo Primate Studies of Leukine

Pharmacology/toxicology studies of Leukine were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day x 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day x 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1-2 week recovery period.

Pharmacokinetics

Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized Leukine, at the recommended dose of 250 mcg/m2, have been determined to be bioequivalent based on the statistical evaluation of AUC.5

When Leukine (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of Leukine infusion. For liquid Leukine, the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m2 and the mean AUC (0–inf) was 640 ng/mL•min. Corresponding results for lyophilized Leukine in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m2, and mean AUC (0–inf) of 677 ng/mL•min. GM-CSF was last detected in blood samples obtained at three or six hours.

When Leukine (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and Leukine remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid Leukine, the mean clearance was 549 mL/min/m2 and the mean AUC (0-inf) was 549 ng/mL•min. For lyophilized Leukine, the mean clearance was 529 mL/min/m2 and the mean AUC (0-inf) was 501 ng/mL•min.

Indications and Usage for Leukine

Use Following Induction Chemotherapy in Acute Myelogenous Leukemia

Leukine is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of Leukine have not been assessed in patients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.

Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progentior Cells

Leukine is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of Leukine following peripheral blood progenitor cell transplantation.

Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation

Leukine is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin's disease, Leukine has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to Leukine can be detected by complete blood count (CBC) with differential cell counts performed twice per week.

Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation

Leukine is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Leukine has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.

Use in Bone Marrow Transplantation Failure or Engraftment Delay

Leukine is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. Leukine has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to Leukine can be detected by complete blood count (CBC) with differential performed twice per week.

CLINICAL EXPERIENCE

Acute Myelogenous Leukemia

The safety and efficacy of Leukine in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of Leukine in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation.6 A combination of standard doses of daunorubicin (days 1–3) and ara-C (days 1–7) was administered during induction and high dose ara-C was administered days 1–6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, Leukine (250 mcg/m2/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/mm3 for three consecutive days was attained or a maximum of 42 days. Leukine or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3–6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.

Leukine significantly shortened the median duration of ANC <500/mm3 by 4 days and <1000/mm3 by 7 days following induction (see Table 1). 75% of patients receiving Leukine achieved ANC >500/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; Leukine significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm3) and RBC transfusion independence were not significantly different between treatment groups.

Table 1 Hematological Recovery (in Days): Induction

* Patients with missing data censored. † p=Generalized Wilcoxon ‡ 2 patients on sargramostim and 4 patients on placebo had missing values. § 2 patients on sargramostim and 3 patients on placebo had missing values. ¶ 4 patients on placebo had missing values. # 3 patients on sargramostim and 4 patients on placebo had missing values.
	Sargramostim n=52* Median (25%, 75%)	Placebo n=47 Median (25%,75%)	p-value†
ANC>500/mm3‡	13 (11, 16)	17 (13, 25)	0.009
ANC>1000/mm3§	14 (12, 18)	21 (13, 34)	0.003
PLT>20,000/mm3¶	11 (7, 14)	12 (9, >42)	0.10
RBC#	12 (9, 24)	14 (9, 42)	0.53

During the consolidation phase of treatment, Leukine did not shorten the median time to recovery of ANC to 500/mm3 (13 days) or 1000/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.

The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received Leukine. During induction or consolidation, 27 of 52 patients receiving Leukine and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving Leukine and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Leukine arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

Disease outcomes were not adversely affected by the use of Leukine. The proportion of patients achieving complete remission (CR) was higher in the Leukine group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received Leukine and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving Leukine and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Leukine treatment on response or survival.

Mobilization and Engraftment of PBPC

A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n=196) receiving Leukine for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received Leukine. The cohorts differed by dose (125 or 250 mcg/m2/day), route (IV over 24 hours or SC) and use of Leukine post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 x 108/kg body weight) and a minimum number of phereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day five, another cytokine was substituted for Leukine; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of Leukine (250 mcg/m2) either IV (n=63) or SC (n=41).

PBPCs from patients treated at the 250 mcg/m2/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 x 104 CFU-GM/kg for all Leukine-mobilized patients, compared to 0.96 x 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 x 104/kg for patients mobilized with 250 mcg/m2 doses of Leukine administered SC vs. 1.63 x 104/kg for non-mobilized patients).

After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm3) was more rapid in patients administered Leukine following PBPC transplantation with Leukine-mobilized cells (see Table 2). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.

Table 2 ANC and Platelet Recovery after PBPC Transplant

	Route for Mobilization	Post-transplant Leukine	ENGRAFTMENT (median value in days)
			ANC>500/mm3	Last platelet transfusion
No Mobilization	—	no	29	28
Leukine 250 mcg/m2	IV	no	21	24
	IV	yes	12	19
	SC	yes	12	17

A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Leukine was given SC at 250 mcg/m2/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of Leukine administration and continued until the targeted MNC count of 9 x 108/kg or CD34+ cell count of 1 x 106/kg was reached. There was no difference in CD34+ cell count in patients receiving Leukine once or twice a day. The median time to ANC>500/mm3 was 12 days and to platelet recovery (>25,000/mm3) was 23 days.

Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.

Autologous Bone Marrow Transplantation7

Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies,8, 9 three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of Leukine for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 Leukine, 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120-150 mg/kg) and total body irradiation (total dose 1,200-1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m2) and carmustine (300 mg/m2), cyclophosphamide (140-150 mg/kg), hydroxyurea (4.5 grams/m2) and etoposide (375-450 mg/m2).

Compared to placebo, administration of Leukine in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of Leukine. This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial Leukine treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.

Table 3 Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials of Responses in Patients with NHL and ALL

Note: The single AML patient was not included.
* p <0.05 Wilcoxon or CMH ridit chi-squared † p <0.05 Log rank
Median Values (days)
	ANC ≥500/mm3	ANC ≥1000/mm3	Duration of Hospitalization	Duration of Infection	Duration of Antibacterial Therapy
Leukine (n=54)	18*†	24*†	25*	1*	21*
Placebo (n=50)	24	32	31	4	25

Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)

Myeloid engraftment (absolute neutrophil count [ANC]≥500 cells/mm3) in 54 patients receiving Leukine was observed 6 days earlier than in 50 patients treated with placebo (see Table 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the Leukine group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with Leukine. The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with Leukine than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post-transplantation. As a group, leukemic subjects receiving Leukine derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving Leukine engrafted earlier than controls.

Patients with Hodgkin's Disease

If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. Leukine-treated patients engrafted earlier (by five days) than the placebo-treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).

Allogeneic Bone Marrow Transplantation

A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Leukine for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Leukine, 56 placebo) were enrolled in the study. Twenty-three patients (11 Leukine, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid.

Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of Leukine significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see Table 4).

Table 4 Allogeneic BMT: Analysis of Data from Placebo-Controlled Clinical Trial

* p <0.05 generalized Wilcoxon test † p <0.05 simple chi-square test
Median Values (days or number of patients)
	ANC ≥ 500/mm3	ANC ≥ 1000/mm3	Number of Patients with Infections	Number of Patients with Bacteremia	Days of Hospitalization
Leukine (n=53)	13*	14*	30*	9†	25*
Placebo (n=56)	17	19	42	19	26

Median time to myeloid engraftment (ANC ≥ 500 cells/mm3) in 53 patients receiving Leukine was 4 four days less than in 56 patients treated with placebo (see Table 4). The number of patients with bacteremia and infection was significantly lower in the Leukine group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the Leukine group (4/53) compared to the placebo group (16/56) at p<0.05. Leukine-treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.

Bone Marrow Transplantation Failure or Engraftment Delay

A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Leukine improved survival after BMT failure.

Three categories of patients were eligible for this study:

1. patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation);


2. patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and


3. patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).

A total of 140 eligible patients from 35 institutions were treated with Leukine and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.

One hundred day survival was improved in favor of the patients treated with Leukine after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with Leukine after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Leukine treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.

The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with Leukine in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see Table 5).

Table 5 Median Survival by Multiple Organ Failure (MOF) Category

Median Survival (days)
	MOF ≤ 2 Organs	MOF > 2 Organs	MOF (Composite of Both Groups)
Autologous BMT
Leukine	474 (n=58)	78.5 (n=10)	474 (n=68)
Historical	165 (n=14)	39 (n=3)	161 (n=17)
Allogeneic BMT
Leukine	174 (n=50)	27 (n=22)	97 (n=72)
Historical	52.5(n=60)	15.5(n=26)	35 (n=86)

Factors that Contribute to Survival

The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.

Contraindications

Leukine is contraindicated:

1. in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);


2. in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product;


3. for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Leukine should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours proceeding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received Leukine and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Leukine. The patients randomized to Leukine had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11

Warnings

Pediatric Use

Benzyl alcohol is a constituent of liquid Leukine and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol (including liquid Leukine ) or lyophilized Leukine reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fluid Retention

Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after Leukine administration. In 156 patients enrolled in placebo-controlled studies using Leukine at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (Leukine vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed Leukine, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of Leukine may aggravate fluid retention; however, fluid retention associated with or worsened by Leukine has been reversible after interruption or dose reduction of Leukine with or without diuretic therapy. Leukine should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms

Sequestration of granulocytes in the pulmonary circulation has been documented following Leukine infusion12 and dyspnea has been reported occasionally in patients treated with Leukine. Special attention should be given to respiratory symptoms during or immediately following Leukine infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during Leukine administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Leukine should be administered with caution in patients with hypoxia.

Cardiovascular Symptoms

Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Leukine administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Leukine. Leukine should be used with caution in patients with preexisting cardiac disease.

Renal and Hepatic Dysfunction

In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Leukine has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Leukine administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between Leukine (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Leukine administration.

Precautions

General

Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, Leukine therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of Leukine in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

Stimulation of marrow precursors with Leukine may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, Leukine administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of Leukine therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.

Growth Factor Potential

Leukine is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that Leukine can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during Leukine treatment, Leukine therapy should be discontinued.

Leukine has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15

Controlled studies have not been performed in patients with MDS.

Use in Patients Receiving Purged Bone Marrow

Leukine is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to Leukine. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of Leukine on myeloid engraftment has been reported.16

Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy

In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of Leukine on myeloid reconstitution may be limited.

Use in Patients with Malignancy Undergoing Leukine-Mobilized PBPC Collection

When using Leukine to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.

Information for Patients

Leukine should be used under t

Meronem IV 500mg & 1g

1. Name Of The Medicinal Product

Meronem IV

2. Qualitative And Quantitative Composition

Meronem IV 500 mg

Each vial contains meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

Meronem IV 1 g

Each vial contains meropenem trihydrate equivalent to 1 g anhydrous meropenem.

Excipients:

Each 500 mg vial contains 104 mg sodium carbonate which equates to approximately 2.0 mEq of sodium (approximately 45 mg).

Each 1 g vial contains 208 mg sodium carbonate which equates to approximately 4.0 mEq of sodium (approximately 90 mg).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection or infusion.

A white to light yellow powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Meronem is indicated for the treatment of the following infections in adults and children over 3 months of age (see sections 4.4 and 5.1):

• Pneumonia, including community acquired pneumonia and nosocomial pneumonia.

• Broncho-pulmonary infections in cystic fibrosis

• Complicated urinary tract infections

• Complicated intra-abdominal infections

• Intra- and post-partum infections

• Complicated skin and soft tissue infections

• Acute bacterial meningitis

Meronem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

The tables below provide general recommendations for dosing.

The dose of meropenem administered and the duration of treatment should take into account the type of infection to be treated, including its severity, and the clinical response.

A dose of up to 2 g three times daily in adults and adolescents and a dose of up to 40 mg/kg three times daily in children may be particularly appropriate when treating some types of infections, such as nosocomial infections due to Pseudomonas aeruginosa or Acinetobacter spp.

Additional considerations for dosing are needed when treating patients with renal insufficiency (see further below).

Adults and Adolescents

Infection	Dose to be administered every 8 hours
Pneumonia including community-acquired pneumonia and nosocomial pneumonia.	500 mg or 1 g
Broncho-pulmonary infections in cystic fibrosis	2 g
Complicated urinary tract infections	500 mg or 1 g
Complicated intra-abdominal infections	500 mg or 1 g
Intra- and post-partum infections	500 mg or 1 g
Complicated skin and soft tissue infections	500 mg or 1 g
Acute bacterial meningitis	2 g
Management of febrile neutropenic patients	1 g

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see section 6.2, 6.3 and 6.6).

Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5 minutes. There are limited safety data available to support the administration of a 2 g dose in adults as an intravenous bolus injection.

Renal impairment

The dose for adults and adolescents should be adjusted when creatinine clearance is less than 51 ml/min, as shown below. There are limited data to support the application of these dose adjustments for a unit dose of 2 g.

Creatinine clearance (ml/min)	Dose (based on “unit” dose range of 500 mg or 1 g or 2 g, see table above)	Frequency
26-50	one unit dose	every 12 hours
10-25	half of one unit dose	every 12 hours
<10	half of one unit dose	every 24 hours

Meropenem is cleared by haemodialysis and haemofiltration. The required dose should be administered after completion of the haemodialysis cycle.

There are no established dose recommendations for patients receiving peritoneal dialysis.

Hepatic impairment

No dose adjustment is necessary in patients with hepatic impairment (see section 4.4).

Dose in elderly patients

No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.

Paediatric population

Children under 3 months of age

The safety and efficacy of meropenem in children under 3 months of age have not been established and the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20 mg/kg every 8 hours may be an appropriate regimen (see section 5.2).

Children from 3 months to 11 years of age and up to 50 kg body weight

The recommended dose regimens are shown in the table below:

Infection	Dose to be administered every 8 hours
Pneumonia including community-acquired pneumonia and nosocomial pneumonia	10 or 20 mg/kg
Broncho-pulmonary infections in cystic fibrosis	40 mg/kg
Complicated urinary tract infections	10 or 20 mg/kg
Complicated intra-abdominal infections	10 or 20 mg/kg
Complicated skin and soft tissue infections	10 or 20 mg/kg
Acute bacterial meningitis	40 mg/kg
Management of febrile neutropenic patients	20 mg/kg

Children over 50 kg body weight

The adult dose should be administered.

There is no experience in children with renal impairment.

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see sections 6.2, 6.3, and 6.6). Alternatively, meropenem doses of up to 20 mg/kg may be given as an intravenous bolus over approximately 5 minutes. There are limited safety data available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity to any other carbapenem antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of betalactam antibacterial agent (e.g. penicillins or cephalosporins).

4.4 Special Warnings And Precautions For Use

The selection of meropenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.

As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8).

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics.

If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate measures taken.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all anti-bacterial agents, including meropenem, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of meropenem (see section 4.8). Discontinuation of therapy with meropenem and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see section 4.8).

Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8).

Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with meropenem. There is no dose adjustment necessary (see section 4.2).

A positive direct or indirect Coombs test may develop during treatment with meropenem.

The concomitant use of meropenem and valproic acid/sodium valproate is not recommended (see section 4.5).

Meronem contains sodium.

Meronem 500 mg: This medicinal product contains approximately 2.0 mEq of sodium per 500 mg dose which should be taken into consideration by patients on a controlled sodium diet.

Meronem 1.0 g: This medicinal product contains approximately 4.0 mEq of sodium per 1.0 g dose which should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific medicinal product interaction studies other than probenecid were conducted.

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem with the effect of increasing the elimination half-life and plasma concentration of meropenem. Caution is required if probenecid is co-administered with meropenem.

The potential effect of meropenem on the protein binding of other medicinal products or metabolism has not been studied. However, the protein binding is so low that no interactions with other compounds would be expected on the basis of this mechanism.

Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100 % decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of valproic acid with carbapenem agents is not considered to be manageable and therefore should be avoided (see section 4.4).

Oral anti-coagulants

Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant agent.

4.6 Pregnancy And Lactation

Pregnancy

There are no or limited amount of data from the use of meropenem in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.

Lactation

It is unknown whether meropenem is excreted in human milk. Meropenem is detectable at very low concentrations in animal breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from meropenem therapy taking into account the benefit of therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effect on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

In a review of 4,872 patients with 5,026 meropenem treatment exposures, meropenem-related adverse reactions most frequently reported were diarrhoea (2.3 %), rash (1.4 %), nausea/vomiting (1.4 %) and injection site inflammation (1.1 %). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6 %) and increased hepatic enzymes (1.5-4.3 %).

Adverse reactions listed in the table with a frequency of “not known” were not observed in the 2,367 patients who were included in pre-authorisation clinical studies with intravenous and intramuscular meropenem but have been reported during the post-marketing period.

In the table below all adverse reactions are listed by system organ class and frequency: very common (

Table 1
System Organ Class	Frequency	Event
Infections and infestations	Uncommon	oral and vaginal candidiasis
Blood and lymphatic system disorders	Common	thrombocythaemia
Uncommon	eosinophilia, thrombocytopenia, leucopenia, neutropenia
Not known	agranulocytosis, haemolytic anaemia
Immune system disorders	Not known	angioedema, anaphylaxis (see sections 4.3 and 4.4)
Nervous system disorders	Common	headache
Uncommon	paraesthesiae
Rare	convulsions (see section 4.4)
Gastrointestinal disorders	Common	diarrhoea, vomiting, nausea, abdominal pain
Not known	antibiotic-associated colitis (see section 4.4)
Hepatobiliary disorders	Common	transaminases increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased.
Uncommon	blood bilirubin increased
Skin and subcutaneous tissue disorders	Common	rash, pruritis
Uncommon	urticaria
Not known	toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme.
Renal and urinary disorders	Uncommon	blood creatinine increased, blood urea increased
General disorders and administration site conditions	Common	inflammation, pain
Uncommon	thrombophlebitis
Not known	pain at the injection site

4.9 Overdose

Relative overdose may be possible in patients with renal impairment if the dose is not adjusted as described in section 4.2. Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the adverse reaction profile described in section 4.8, are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered.

In individuals with normal renal function, rapid renal elimination will occur.

Haemodialysis will remove meropenem and its metabolite.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antibacterials for systemic use, carbapenems

ATC code: J01DH02

Mode of action

Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40 % of the dosing interval. This target has not been established clinically.

Mechanism of resistance

Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyse carbapenems.

Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European Union.

There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more than one class of antibacterials agents when the mechanism involved include impermeability and/or an efflux pump(s).

Breakpoints

European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below.

EUCAST clinical MIC breakpoints for meropenem (2009-06-05, v 3.1)

Organism	Susceptible (S) (mg/l)	Resistant (R) (mg/l)
Enterobacteriaceae		> 8
Pseudomonas		> 8
Acinetobacter		> 8
Streptococcus groups A, B, C, G		> 2
Streptococcus pneumoniae1		> 2
Other streptococci	2	2
Enterococcus	--	--
Staphylococcus2	note 3	note 3
Haemophilus influenzae1 and Moraxella catarrhalis		> 2
Neisseria meningitidis2, 4		> 0.25
Gram-positive anaerobes		> 8
Gram-negative anaerobes		> 8
Non-species related breakpoints5		> 8

¹ Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25/1 mg/L.

² Strains with MIC values above the S/I breakpoint are rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported as resistant.

³ Susceptibility of staphylococci to meropenem is inferred from the methicillin susceptibility.

⁴ Meropenem breakpoints in Neisseria meningitidis relates to meningitis only.

⁵ Non-species related breakpoints have been determined mainly from PK/PD data and are independent of the MIC distributions of specific species. They are for use for species not mentioned in the table and footnotes.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

The following table of pathogens listed is derived from clinical experience and therapeutic guidelines.

Commonly susceptible species

Gram-positive aerobes

Enterococcus faecalis^$

Staphylococcus aureus (methicillin-susceptible)^£

Staphylococcus species (methicillin-susceptible) including Staphylococcus epidermidis

Streptococcus agalactiae (Group B)

Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius)

Streptococcus pneumoniae

Streptococcus pyogenes (Group A)

Gram-negative aerobes

Citrobacter freudii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Morganella morganii

Neisseria meningitides

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Gram-positive anaerobes

Clostridium perfringens

Peptoniphilus asaccharolyticus

Peptostreptococcus species (including P. micros, P anaerobius, P. magnus)

Gram-negative anaerobes

Bacteroides caccae

Bacteroides fragilis group

Prevotella bivia

Prevotella disiens

Species for which acquired resistance may be a problem

Gram-positive aerobes

Enterococcus faecium^$†

Gram-negative aerobes

Acinetobacter species

Burkholderia cepacia

Pseudomonas aeruginosa

Inherently resistant organisms

Gram-negative aerobes

Stenotrophomonas maltophilia

Legionella species

Other micro-organisms

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetii

Mycoplasma pneumoniae

^$ Species that show natural intermediate susceptibility

^£ All methicillin-resistant staphylococci are resistant to meropenem

^† Resistance rate

5.2 Pharmacokinetic Properties

In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/ml. After infusion over 5 minutes Cmax values are 52 and 112 μg/ml after 500 and 1000 mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.

A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27 l.

Distribution

The average plasma protein binding of meropenem was approximately 2 % and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates.

Metabolism

Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.

Elimination

Meropenem is primarily excreted unchanged by the kidneys; approximately 70 % (50 –75 %) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

Renal insufficiency

Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC increases of 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min), 5 fold in severe impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL <2 ml/min) when compared to healthy subjects (CrCL >80 ml/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment (see section 4.2).

Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher than in anuric patients.

Hepatic insufficiency

A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.

Adult patients

Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age.

Paediatrics

The pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The mean meropenem clearance values were 5.8 ml/min/kg (6-12 years), 6.2 ml/min/kg (2-5 years), 5.3 ml/min/kg (6-23 months) and 4.3 ml/min/kg (2-5 months). Approximately 60 % of the dose is excreted in urine over 12 hours as meropenem with a further 12 % as metabolite. Meropenem concentrations in the CSF of children with meningitis are approximately 20 % of concurrent plasma levels although there is significant inter-individual variability.

The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9 hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hourly achieved 60 %T>MIC for P. aeruginosa in 95 % of pre-term and 91 % of full term neonates.

Elderly

Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment (see section 4.2).

5.3 Preclinical Safety Data

Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2000 mg/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.

Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000 mg/kg.

The IV LD₅₀ of meropenem in rodents is greater that 2000 mg/kg.

In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.

There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.

There was increased evidence of abortions at 500 mg/kg in a preliminary study in monkeys.

There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.

The sole metabolite of meropenem had a similar profile of toxicity in animal studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Meronem 500 mg: anhydrous sodium carbonate

Meronem 1 g: anhydrous sodium carbonate

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

4 years

After reconstitution:

Intravenous bolus injection administration

A solution for bolus injection is prepared by dissolving the drug product Meronem in water for injection to a final concentration of 50 mg/ml.

Chemical and physical in-use stability for a prepared solution for bolus injection has been demonstrated for 3 hours at controlled room temperature (15-25°C).

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately.

If not used immediately in-use storage times and conditions are the responsibility of the user.

Intravenous infusion administration

A solution for infusion is prepared by dissolving the drug product Meronem in either 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a final concentration of 1 to 20 mg/ml.

Chemical and physical in-use stability for a prepared solution for infusion using 0.9% sodium chloride solution has been demonstrated for 6 hours at controlled room temperature (15-25°C) or 24 hours at 2-8°C. The prepared solution should, if refrigerated, be used within 2 hours after it has left the refrigerator. From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately in-use storage times and conditions are the responsibility of the user.

Reconstituted solution of Meronem in 5% glucose (dextrose) solution should be used immediately, i.e. within one hour following reconstitution.

6.4 Special Precautions For Storage

Do not store above 30°C.

Do not freeze the reconstituted solution.

6.5 Nature And Contents Of Container

Meronem 500 mg

674 mg powder in a 20 ml Type 1 glass vial with stopper (grey halobutilic rubber with an aluminium cap)

Meronem 1 g

1348 mg powder in a 30 ml Type 1 glass vial with stopper (grey halobutilic rubber with an aluminium cap)

The medicinal product is supplied in pack sizes of 1 or 10 vials.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Injection

Meropenem to be used for bolus intravenous injection should be constituted with sterile water for injection.

Infusion

For intravenous infusion meropenem vials may be directly constituted with 0.9 % sodium chloride or 5% glucose solutions for infusion.

Each vial is for single use only.

Standard aseptic techniques should be used for solution preparation and administration.

The solution should be shaken before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

AstraZeneca UK Ltd

600 Capability Green

Luton

LU1 3LU

United Kingdom

8. Marketing Authorisation Number(S)

Meronem IV 500 mg	PL 17901/0029
Meronem IV 1 g	PL 17901/0030

9. Date Of First Authorisation/Renewal Of The Authorisation

09 February 2009

10. Date Of Revision Of The Text

21 November 2011