Clotrimazole Lozenge

Dosage Form: troche, lozenge
Clotrimazole Lozenge

(Clotrimazole Troche)

FOR TOPICAL ORAL ADMINISTRATION

Clotrimazole Lozenge Description

Each Clotrimazole Lozenge contains 10 mg clotrimazole [1-(o-chloro-α, α-diphenylbenzyl) imidazole], a synthetic antifungal agent, for topical use in the mouth.

Structural Formula:

Chemical Formula:

C22H17ClN2

The lozenge dosage form is a large, slowly dissolving tablet (troche) containing 10 mg of clotrimazole dispersed in dextrose, microcrystalline cellulose, povidone, and magnesium stearate.

Clotrimazole Lozenge - Clinical Pharmacology

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by altering the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Candida albicans in the laboratory; however, individual organism tolerance has been observed during successive passages in the laboratory. Such in vitro tolerance has resolved once the organism has been removed from the antifungal environment.

After oral administration of a 10 mg Clotrimazole Lozenge to healthy volunteers, concentrations sufficient to inhibit most species of Candida persist in saliva for up to three hours following the approximately 30 minutes needed for a lozenge to dissolve. The long term persistence of drug in saliva appears to be related to the slow release of clotrimazole from the oral mucosa to which the drug is apparently bound. Repetitive dosing at three hour intervals maintains salivary levels above the minimum inhibitory concentrations of most strains of Candida; however, the relationship between in vitro susceptibility of pathogenic fungi to clotrimazole and prophylaxis or cure of infections in humans has not been established.

In another study, the mean serum concentrations were 4.98 ± 3.7 and 3.23 ± 1.4 nanograms/mL of clotrimazole at 30 and 60 minutes, respectively, after administration as a lozenge.

Indications and Usage for Clotrimazole Lozenge

Clotrimazole Lozenges are indicated for the local treatment of oropharyngeal candidiasis. The diagnoses should be confirmed by a KOH smear and/or culture prior to treatment.

Clotrimazole Lozenges are also indicated prophylactically to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation. There are no data from adequate and well-controlled trials to establish the safety and efficacy of this product for prophylactic use in patients immunocompromised by etiologies other than those listed in the previous sentence. (See DOSAGE AND ADMINISTRATION.)

Contraindications

Clotrimazole Lozenges are contraindicated in patients who are hypersensitive to any of its components.

Warning

Clotrimazole Lozenges are not indicated for the treatment of systemic mycoses including systemic candidiasis.

Precautions

Abnormal liver function tests have been reported in patients treated with Clotrimazole Lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials. In most cases the elevations were minimal and it was often impossible to distinguish effects of clotrimazole from those of other therapy and the underlying disease (malignancy in most cases). Periodic assessment of hepatic function is advisable particularly in patients with pre-existing hepatic impairment.

Since patients must be instructed to allow each lozenge to dissolve slowly in the mouth in order to achieve maximum effect of the medication, they must be of such an age and physical and/or mental condition to comprehend such instructions.

Carcinogenesis:

An 18 month dosing study with clotrimazole in rats has not revealed any carcinogenic effect.

Usage in Pregnancy:

Pregnancy Category C:

Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose.

Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability.

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

PEDIATRIC USE

Safety and effectiveness of clotrimazole in children below the age of 3 years have not been established; therefore, its use in such patients is not recommended.

The safety and efficacy of the prophylactic use of Clotrimazole Lozenges in children have not been established.

GERIATRIC USE

Clinical studies of clotrimazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Adverse Reactions

Abnormal liver function tests have been reported in patients treated with Clotrimazole Lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials (See Precautions section).

Nausea, vomiting, unpleasant mouth sensations and pruritus have also been reported with the use of the lozenge.

Overdosage

No data available.

Drug Abuse and Dependence

No data available.

Clotrimazole Lozenge Dosage and Administration

Clotrimazole Lozenges must be slowly dissolved in the mouth. The recommended dose is one lozenge five times a day for fourteen consecutive days. Only limited data are available on the safety and effectiveness of the Clotrimazole Lozenge after prolonged administration; therefore, therapy should be limited to short term use, if possible.

For prophylaxis to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation, the recommended dose is one lozenge three times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.

How is Clotrimazole Lozenge Supplied

Clotrimazole Lozenges, 10 mg, white discoid, uncoated tablets, debossed with "PAD" over "0107" on one side and plain on the other, are supplied as follows:

	Strength	NDC Code	Lozenge Identification
Bottles of 70:	10 mg	0574-0107-70	PAD 0107
Bottles of 140:	10 mg	0574-0107-14	PAD 0107
Boxes of 70 foil packs:	10 mg	0574-0107-77	PAD 0107

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]

Avoid freezing.

Paddock Laboratories, Inc.

Minneapolis, MN 55427

(02-08)

PRINCIPAL DISPLAY PANEL - 70 Lozenge Box

NDC 0574-0107-70

CLOTRIMAZOLE

LOZENGE

(Clotrimazole Troche)

10 mg

Rx ONLY

DOSAGE: Each lozenge

must be dissolved

slowly in the mouth.

NET CONTENTS

70 LOZENGES

Paddock

Laboratories, Inc.

CLOTRIMAZOLE  clotrimazole  lozenge

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0574-0107 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength clotrimazole (clotrimazole) clotrimazole 10 mg

Inactive Ingredients Ingredient Name Strength dextrose   cellulose, microcrystalline   povidone   magnesium stearate

Product Characteristics Color WHITE Score no score Shape ROUND Size 16mm Flavor Imprint Code PAD;0107 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0574-0107-70 70 LOZENGE In 1 BOTTLE, PLASTIC None 2 0574-0107-14 140 LOZENGE In 1 BOTTLE, PLASTIC None 3 0574-0107-77 70 PACKET In 1 BOX contains a PACKET 3 1 LOZENGE In 1 PACKET This package is contained within the BOX (0574-0107-77)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076763	12/01/2005

Labeler - Paddock Laboratories, Inc. (086116803)

Establishment
Name	Address	ID/FEI	Operations
Paddock Laboratories, Inc.		086116803	MANUFACTURE

Revised: 11/2010Paddock Laboratories, Inc.

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Xigris 20mg powder for solution for infusion, 5mg powder for solution for infusion

1. Name Of The Medicinal Product

Xigris* 5mg powder for solution for infusion.

Xigris 20mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Xigris 5mg: Each vial contains 5mg of Drotrecogin alfa (activated).

After reconstitution with 2.5ml of Water for Injection each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 17mg sodium.

Xigris 20mg: Each vial contains 20mg of drotrecogin alfa (activated).

After reconstitution with 10ml of Water for Injection, each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 68mg sodium.

Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion. Xigris is supplied as a lyophilised, white to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see section 5.1).

4.2 Posology And Method Of Administration

Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis.

Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see section 5.1).

The recommended dose of Xigris is 24μg/kg/hr (based on actual body weight) given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24μg/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion.

No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels), renal function, obesity or co-administration of prophylactic heparin. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and pre-existing end-stage renal disease and chronic hepatic disease.

Paediatrics: Data from a placebo-controlled clinical trial, which was stopped for futility after 477 patients 0 to 17 years old had received the study treatment, did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group. Xigris is contraindicated in children below the age of 18 (see sections 4.3 and 5.1).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, or to bovine thrombin (a trace residue from the manufacturing process).

Drotrecogin alfa (activated) is contraindicated in children below the age of 18 years (see section 5.1).

Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations:

• Active internal bleeding. • Patients with intracranial pathology; neoplasm or evidence of cerebral herniation. • Concurrent heparin therapy • Known bleeding diathesis except for acute coagulopathy related to sepsis. • Chronic severe hepatic disease. • Platelet count <30,000 x 106 /l, even if the platelet count is increased after transfusions. • Patients at increased risk for bleeding (for example):

a) Any major surgery, defined as surgery that requires general or spinal anaesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period. b) History of severe head trauma that required hospitalisation, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion. c) History of congenital bleeding diatheses. d) Gastro-intestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed. e) Trauma patients at increased risk of bleeding.

4.4 Special Warnings And Precautions For Use

No further study has confirmed the efficacy results of the single pivotal trial.

Patients With Single Organ Dysfunction and Recent Surgery

Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 28-day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n = 98 in PROWESS and n = 636 in ADDRESS).

Bleeding

Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits:

• Recent administration (within 3 days) of thrombolytic therapy.

• Recent administration (within 7 days) of oral anticoagulants.

• Recent administration (within 7 days) of aspirin or other platelet inhibitors.

• Recent (within 3 months) ischaemic stroke.

• Any other condition in which the physician considers significant bleeding is likely.

For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate haemostasis has been achieved. The incidence of serious bleeding events with Xigris was higher in patients with recent (within 30 days) surgery than in “medical” patients without surgery (see section 4.8). Bleeding risk should be taken into account when considering the risk benefit for individual patients. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved.

As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time [APTT], prothrombin time [PT], and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient.

Laboratory Tests

Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medicinal products. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralised by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration.

Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as Factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factor II, V, VII and X assays).

If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit.

Immunogenicity

In adult patients in severe sepsis clinical studies, the frequency of anti-human Activated Protein C IgA/IgG/IgM antibodies or neutralising antibodies is low and is similar between drotrecogin alfa (activated) and placebo-treated patients tested. In patients developing antibodies, adverse events were not more frequent in drotrecogin alfa (activated) than in placebo patients. There was no evidence that the antibodies detected represented a specific immune response to drotrecogin alfa (activated) therapy.

There have been no clinical trials in severe sepsis specifically studying drotrecogin alfa (activated) re-administration. However, a small number of patients in severe sepsis controlled clinical trials received a prior course of drotrecogin alfa (activated). No hypersensitivity reactions were reported in these patients. Samples available were subsequently tested and all were negative for anti-human Activated Protein C antibody.

No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration.

However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. If Xigris is readministered to patients, caution should be employed.

Xigris 5mg: This medicinal product contains approximately 17mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Xigris 20mg: This medicinal product contains approximately 68mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be employed when Xigris is used with other drugs that affect haemostasis (see sections 4.3 and 4.4), including Protein C, thrombolytics (e.g., streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g., warfarin), hirudins, antithrombin, aspirin and other anti-platelets agents, e.g., non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins, such as iloprost.

Co-administration of Low-dose Heparin for Prophylaxis of Venous Thrombotic Events (VTE)

Low-dose heparin for VTE prophylaxis may be co-administered with drotrecogin alfa (activated). In a randomised study of heparin versus placebo (XPRESS) in 1,935 adult severe sepsis patients, all treated with drotrecogin alfa (activated), prophylactic heparin did not adversely affect mortality (heparin 28.3% versus placebo 31.9% in the overall ITT population, and heparin 30.3% versus placebo 26.9% in patients with multiple organ dysfunction treated within 24 hours of their first sepsis-induced organ dysfunction (n=890)). In the subgroup of 885 patients who were already receiving prophylactic heparin at study entry, mortality was 26.9% in the group randomised to continue heparin versus 35.6% in the group whose randomisation (to placebo) led to the discontinuation of heparin. However, the reasons for this difference are unknown and could be related to other factors. Additionally, there was no increased risk of serious bleeding, including central nervous system (CNS) bleeding. Prophylactic heparin increased the risk of non-serious bleeding (see section 4.8). There was no statistical difference in the rates of VTE between study arms.

4.6 Pregnancy And Lactation

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition, and post-natal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary.

It is not known whether Xigris is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast-feed whilst treated with Xigris.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Xigris increases the risk of bleeding.

The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastro-intestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.

A total of 2,378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE).

The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies, serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of

A Phase 3b, international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death involved 1,317 drotrecogin alfa (activated)-treated and 1,293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (P <0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator.

Serious Bleeding Events During the Infusion Period

The following table lists the percentage of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).

Site of Haemorrhage	Drotrecogin Alfa (Activated) [PROWESS] n = 850	Placebo [PROWESS] n = 840	Drotrecogin Alfa (Activated) [ENHANCE] n = 2,378
Gastro-intestinal	5 (0.6%)	4 (0.5%)	19 (0.8%)
Intra-abdominal	2 (0.2%)	3 (0.4%)	18 (0.8%)
Intra-thoracic	4 (0.5%)	0	11 (0.5%)
Retroperitoneal	3 (0.4%)	0	4 (0.2%)
Central nervous system (CNS)1	2 (0.2%)	0	15 (0.6%)
Genito-urinary	2 (0.2%)	0	0
Skin/soft tissue	1 (0.1%)	0	16 (0.7%)
Nasopharyngeal	0	0	4 (0.2%)
Joint/bone	0	0	1 (0.04%)
Site unknown2	1 (0.1%)	1 (0.1%)	6 (0.3%)
Total	20 (2.4%)	8 (1.0%)	853 (3.6%)
1 CNS bleeding is defined as any bleed in the central nervous system, including the following types of haemorrhage: petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation. 2 Patients requiring the administration of 3 In ENHANCE, six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).

During the infusion period in PROWESS and ENHANCE, the incidence of serious bleeding events with Xigris was numerically higher in patients with recent (within 30 days) surgery than in patients without surgery (PROWESS: 3.3% versus 2.0%; ENHANCE: 5.0% versus 3.1% respectively. Placebo rates in PROWESS 0.4% versus 1.2% respectively).

In ADDRESS, the percentage of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study day 0 through study day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9%, respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% versus 2.5%, respectively), including CNS bleeding (0.3% on both arms). However, prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% versus 5.7%, respectively; P = 0.0116).

Serious Bleeding Events During the 28-Day Study Period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4).

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS, serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% versus 5.2%, respectively), including CNS bleeding (1.0% versus 0.7%, respectively).

In the Phase 1 studies, adverse events with a frequency of

4.9 Overdose

In clinical trials and in post-marketing experience there have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis.

There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see section 5.2).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agents, enzymes. ATC code: B01AD10.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year, and this SPC will be updated as necessary.

Mechanism of Action

Xigris is a recombinant version of the natural plasma-derived Activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating Factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C.

Pharmacodynamic Effects

In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers, such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels, and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.

Clinical Efficacy

Xigris was studied in one Phase 3, international, multi-centre, randomised, double-blind, placebo-controlled trial (PROWESS) in 1,690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had: a) known or suspected infection; b) clinical evidence of systemic response to infection, including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea; and c) acute organ dysfunction. Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal [PaO₂/FiO₂ ratio] <250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations.

Exclusion criteria encompassed patients at high risk of bleeding (see sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD₄ count was ³, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection.

In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24μg/kg/hr (n = 850) or placebo (n = 840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required).

Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (P = 0.005).

Significant absolute death reduction was limited to the subgroup of patients with greater disease severity, i.e., baseline APACHE II score

A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender, and infection type.

PROWESS Follow-Up Study

Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3-month survival status was reported for 98% and 94% of the 1,690 PROWESS subjects, respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% versus 34.6%; P = 0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank P = 0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients, such as patients with multiple organ failure and shock.

Further Clinical Experience

In a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE), 2,378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity.

A total of 2,640 adult patients with severe sepsis who were at low risk of death (e.g., patients with APACHE II <25 or with only one sepsis-induced organ failure) were enrolled in a randomised, double-blind, placebo-controlled trial (ADDRESS). The trial was stopped for futility after an interim analysis.

No benefit of drotrecogin alfa (activated) was observed in the subgroup of 872 patients at low risk of death with multiple organ dysfunction, so ADDRESS did not confirm the efficacy results of the PROWESS study.

In the multiple organ dysfunction subgroup of ADDRESS the 28-day placebo mortality was 21.9%, similar to the single organ dysfunction subgroup of PROWESS (21.2%), confirming the lack of efficacy in patients with severe sepsis who are at low risk of death.

Paediatric Patients

Xigris is contraindicated in children below the age of 18 years (see also sections 4.2 and 4.3).

Data from a placebo-controlled clinical trial (RESOLVE) did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively).

Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients

In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients.

5.2 Pharmacokinetic Properties

Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors, but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).

In healthy subjects, greater than 90% of the steady-state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t_½α = 13 minutes) and a slower second phase (t_½β = 1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12μg/kg/hr to 48μg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24μg/kg/hr is 72ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12μg/kg/hr to 30μg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.

In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.

5.3 Preclinical Safety Data

Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies were all related to the pharmacological effect of Xigris and include, beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit and increases in reticulocyte count and PT.

Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Sodium chloride

Sodium citrate

Citric acid

Hydrochloric acid

Sodium hydroxide

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

3 years.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15ºC- 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15ºC- 30ºC) for a period up to 14 hours.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

Powder in Type I glass vial. Pack of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

1.	Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.
2.	Calculate the dose and the number of Xigris vials needed.
	Xigris 5mg: Each Xigris vial contains 5mg of drotrecogin alfa (activated).
	Xigris 20mg: Each Xigris vial contains 20mg of drotrecogin alfa (activated).
	The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.
3.	Xigris 5mg: Prior to administration, 5mg vials of Xigris must be reconstituted with 2.5ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).
	Xigris 20mg: Prior to administration, 20mg vials of Xigris must be reconstituted with 10ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).
	Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.
4.	The solution of reconstituted Xigris must be further diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100μg/ml and 200μg/ml. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% sodium chloride injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.
5.	After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC).
	After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours.
6.	Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
7.	It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100µg/ml and 200µg/ml.
8.	When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5ml/hr.
9.	Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer's injection, dextrose, or dextrose and saline mixtures.
10.	Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered.
11.	Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.

7. Marketing Authorisation Holder

Eli Lilly Nederland BV, Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

5mg vial:	EU/1/02/225/001
20mg vial:	EU/1/02/225/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:	22 August 2002
Date of latest renewal:

Ismelin

guanethidine monosulfate

Dosage Form: Tablets

Ismelin®

guanethidine monosulfate USP

C96-14 (Rev. 3/96) 666671

Tablets

Prescribing Information

DESCRIPTION

Ismelin, guanethidine monosulfate USP, is an antihypertensive, available as tablets of 10 mg and 25 mg for oral administration. Each 10-mg and 25-mg tablet contains guanethidine monosulfate USP equivalent to 10 mg and 25 mg of guanethidine sulfate USP. Its chemical name is [2-(hexahydro-1(2H)-azocinyl)ethyl]guanidine sulfate 1:1, and its structural formula is

Guanethidine monosulfate USP is a white to off-white crystalline powder with a molecular weight of 296.38. It is very soluble in water, sparingly soluble in alcohol, and practically insoluble in chloroform.

Inactive Ingredients. Calcium stearate, colloidal silicon dioxide, D&C Yellow No. 10 (10-mg tablets), lactose, starch, stearic acid, and sucrose.

CLINICAL PHARMACOLOGY

Ismelin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of the chemical mediator (presumably the catecholamine norepinephrine), rather than acting at the effector cell by inhibiting the association of the transmitter with its receptors. In contrast to ganglionic blocking agents, Ismelin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Ismelin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more. The inhibition of sympathetic venoconstrictive mechanisms results in venous pooling of blood. Therefore, the effect of Ismelin is especially pronounced when the patient is standing. Both the systolic and diastolic pressures are reduced.

Other actions at the sympathetic nerve terminal include depletion of norepinephrine. Once it gains access to the neuron, Ismelin accumulates within the intraneuronal storage vesicles and causes depletion of norepinephrine stores within the nerve terminal. Prolonged oral administration of Ismelin produces a denervation sensitivity of the neuroeffector junction, probably resulting from the chronic reduction in norepinephrine released by the sympathetic nerve endings. Systemic responses to catecholamines released from the adrenal medulla are not prevented and may even be augmented as a result of this denervation sensitivity. A paradoxical hypertensive crisis may occur if Ismelin is given to patients with pheochromocytoma or if norepinephrine is given to a patient receiving the drug.

Due to its poor lipid solubility, Ismelin does not readily cross the blood-brain barrier. In contrast to most neural blocking agents, Ismelin does not appear to suppress plasma renin activity in many patients.

Pharmacokinetics

The pharmacokinetics of Ismelin are complex. The amount of drug in plasma and in urine is linearly related to dose, although large differences occur between individuals because of variation in absorption and metabolism. Adrenergic blockade occurs with a minimum concentration in plasma of 8 ng/ml; this concentration is achieved in different individuals with dosages of 10-50 mg/day at steady state. Ismelin is eliminated slowly because of extensive tissue binding. After chronic oral administration, the initial phase of elimination with a half-life of 1.5 days is followed by a second phase of elimination with a half-life of 4-8 days. The renal clearance of Ismelin is 56 ml/min. Ismelin is converted by the liver to three metabolites, which are excreted in the urine. The metabolites are pharmacologically less active than Ismelin.

INDICATIONS AND USAGE

Ismelin is indicated for the treatment of moderate and severe hypertension, either alone or as an adjunct, and for the treatment of renal hypertension, including that secondary to pyelonephritis, renal amyloidosis, and renal artery stenosis.

CONTRAINDICATIONS

Known or suspected pheochromocytoma; hypersensitivity; frank congestive heart failure not due to hypertension; use of monoamine oxidase (MAO) inhibitors.

WARNINGS

Ismelin is a potent drug and its use can lead to disturbing and serious clinical problems. Before prescribing, physicians should familiarize themselves with the details of its use and warn patients not to deviate from instructions.

Orthostatic hypotension can occur frequently, and patients should be properly instructed about this potential hazard. Fainting spells may occur unless the patient is forewarned to sit or lie down with the onset of dizziness or weakness. Postural hypotension is most marked in the morning and is accentuated by hot weather, alcohol, or exercise. Dizziness or weakness may be particularly bothersome during the initial period of dosage adjustment and with postural changes, such as arising in the morning. The potential occurrence of these symptoms may require alteration of previous daily activity. The patient should be cautioned to avoid sudden or prolonged standing or exercise while taking the drug.

Inhibition of ejaculation has been reported in animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility) as well as in men given Ismelin. This effect, which results from the sympathetic blockade caused by the drug's action, is reversible after Ismelin has been discontinued for several weeks. The drug does not cause parasympathetic blockade, and erectile potency is usually retained during administration of Ismelin. The possible occurrence of inhibition of ejaculation should be kept in mind when considering the use of guanethidine in men of reproductive age.

If possible, therapy should be withdrawn 2 weeks prior to surgery to reduce the possibility of vascular collapse and cardiac arrest during anesthesia. If emergency surgery is indicated, preanesthetic and anesthetic agents should be administered cautiously in reduced dosage. Oxygen, atropine, vasopressors, and adequate solutions for volume replacement should be ready for immediate use to counteract vascular collapse in the surgical patient. Vasopressors should be used only with extreme caution, since Ismelin augments responsiveness to exogenously administered norepinephrine and vasopressors; specifically, blood pressure may rise and cardiac arrhythmias may be produced.

PRECAUTIONS

General

Dosage requirements may be reduced in the presence of fever.

Special care should be exercised when treating patients with a history of bronchial asthma; asthmatic patients are more apt to be hypersensitive to catecholamine depletion, and their condition may be aggravated.

The effects of Ismelin are cumulative over long periods; initial doses should be small and increased gradually in small increments.

Ismelin should be used very cautiously in hypertensive patients with: renal disease and nitrogen retention or rising BUN levels, since decreased blood pressure may further compromise renal function; coronary insufficiency or recent myocardial infarction; and cerebrovascular disease, especially with encephalopathy.

Ismelin should not be given to patients with severe cardiac failure except with extreme caution, since Ismelin may interfere with the compensatory role of the adrenergic system in producing circulatory adjustment in patients with congestive heart failure.

Patients with incipient cardiac decompensation should be watched for weight gain or edema, which may be averted by the concomitant administration of a thiazide.

Ismelin should be used cautiously in patients with a history of peptic ulcer or other chronic disorders that may be aggravated by a relative increase in parasympathetic tone.

Information for Patients

The patient should be advised to take Ismelin exactly as directed. If the patient misses a dose, he or she should be told to take only the next scheduled dose (without doubling it).

The patient should be advised to avoid sudden or prolonged standing or exercise and to arise slowly, especially in the morning, to reduce the orthostatic hypotensive effects of dizziness, lightheadedness, or fainting.

The patient should be cautioned about ingesting alcohol, since it aggravates the orthostatic hypotensive effects of Ismelin.

Male patients should be advised that guanethidine may interfere with ejaculation.

Drug Interactions

Concurrent use of Ismelin and rauwolfia derivatives may cause excessive postural hypotension, bradycardia, and mental depression.

Both digitalis and Ismelin slow the heart rate.

Thiazide diuretics enhance the antihypertensive action of Ismelin (see DOSAGE AND ADMINISTRATION).

Amphetamine-like compounds, stimulants (e. g., ephedrine, methylphenidate), tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine) and other psychopharmacologic agents (e.g., phenothiazines and related compounds), as well as oral contraceptives, may reduce the hypotensive effect of Ismelin.

MAO inhibitors should be discontinued for at least 1 week before starting therapy with Ismelin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with Ismelin.

While inhibition of sperm passage and accumulation of sperm debris have been reported in rats and rabbits after several weeks of administration of Ismelin, 5 or 10 mg/kg per day, subcutaneously or intraperitoneally, recovery of ejaculatory function and fertility has been demonstrated in rats given Ismelin intramuscularly, 25 mg/kg per day, for 8 weeks. Inhibition of ejaculation has also been reported in men (see WARNINGS and ADVERSE REACTIONS). This effect, which is attributable to the sympathetic blockade caused by the drug, is reversible several weeks after discontinuance of the drug.

Pregnancy Category C

Animal reproduction studies have not been conducted with Ismelin. It is also not known whether Ismelin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ismelin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Ismelin is excreted in breast milk in very small quantity. Caution should be exercised when Ismelin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency. Consequently the reactions are categorized by organ system and are listed in decreasing order of severity and not frequency.

Digestive: Diarrhea, which may be severe at times and necessitate discontinuance of medication; vomiting; nausea: increased bowel movements; dry mouth: parotid tenderness.

Cardiovascular: Chest pains (angina): bradycardia; a tendency toward fluid retention and edema with occasional development of congestive heart failure

Respiratory: Dyspnea; asthma in susceptible individuals: nasal congestion.

Neurologic: Syncope resulting from either postural or exertional hypotension; dizziness; blurred vision, muscle tremor; ptosis of the lids; mental depression; chest paresthesias; weakness; lassitude; fatigue.

Muscular: Myalgia.

Genitourinary: Rise in BUN; urinary incontinence; inhibition of ejaculation; nocturia.

Metabolic: Weight gain.

Skin and Appendages: Dermatitis; scalp hair loss.

Although a causal relationship has not been established. a few instances of blood dyscrasias (anemia, thrombocytopenia, and leukopenia) and of priapism or impotence have been reported.

OVERDOSAGE

Acute Toxicity

No deaths due to acute poisoning have been reported.

Oral LD50 in rats: 1262 mg/kg.

Signs and Symptoms

Postural hypotension (with dizziness, blurred vision, and possibly syncope when standing), shock, and bradycardia are most likely to occur; diarrhea (possibly severe), nausea, and vomiting may also occur. Unconsciousness is unlikely if adequate blood pressure and cerebral perfusion can be maintained by placing the patient in the supine position and by administering other treatment as required.

Treatment

There is no specific antidote.

Treatment should consist of gastric lavage. An activated charcoal slurry should be instilled and laxatives given, if conditions permit.

In sinus bradycardia, atropine should be administered.

In previously normotensive patients, treatment has consisted essentially of restoring blood pressure and heart rate to normal by keeping the patient in the supine position. Normal homeostatic control usually returns gradually over a 72-hour period in these patients.

In previously hypertensive patients, particularly those with impaired cardiac reserve or other cardiovascular- renal disease, intensive treatment may be required to support vital functions and to control cardiac irregularities that might be present. The supine position must be maintained; if vasopressors are required, they must be used with extreme caution, since Ismelin may increase responsiveness, causing a rise in blood pressure and development of cardiac arrhythmias.

Diarrhea, if severe or persistent, should be treated with anticholinergic agents to reduce intestinal hypermotility; hydration and electrolyte balance should be maintained.

Since Ismelin is excreted slowly, cardiovascular and renal function should be monitored for a few days.

DOSAGE AND ADMINISTRATION

Better control may be obtained, especially in the initial phases of treatment, if the patient can have his blood pressure recorded regularly at home.

Ambulatory Patients

Initial doses should be small (10 mg) and increased gradually, depending upon the patient's response. Ismelin has a long duration of action; therefore, dosage increases should not be made more often than every 5-7 days, unless the patient is hospitalized.

Blood pressure should be measured in the supine position, after standing for 10 minutes, and immediately after exercise if feasible. Dosage may be increased only if there has been no decrease in the standing blood pressure from previous levels. The average daily dose is 25-50 mg; only one dose a day is usually required.

Dosage Chart for Ambulatory Patients

Visits (intervals of 5 - 7 Days)                                    Daily Dose

Visit 1 (Patient may be started on 10-mg tablets)............................................................ 10 mg

Visit 2 ...............................................................................................................................20 mg

Visit 3 (Patient may be changed to 25-mg tablets whenever convenient)....................... 30 mg (three 10-mg tablets) or 37.5 mg (one and one-half 25-mg tablets)

Visit 4 .............................................................................................................................. 50 mg

Visit 5 and subsequent........................... Dosage may be increased by 12.5 mg or 25 mg if necessary.

The dosage should be reduced in any of the following situations: (1) normal supine pressure: (2) excessive orthostatic fall in pressure; (3) severe diarrhea.

Hospitalized Patients

Initial oral dose is 25-50 mg, increased by 25 mg or 50 mg daily or every other day, as indicated. This higher dosage is possible because hospitalized patients can be watched carefully. Unless absolutely impossible, the standing blood pressure should be measured regularly. Patients should not be discharged from the hospital until the effect of the drug on the standing blood pressure is known. Patients should be told about the possibility of orthostatic hypotension and warned not to get out of bed without help during the period of dosage adjustment.

Combination Therapy

Ismelin may be added gradually to thiazides and/or hydralazine. Thiazide diuretics enhance the effectiveness of Ismelin and may reduce the incidence of edema. When thiazide diuretics are added to the regimen in patients taking Ismelin, it is usually necessary to reduce the dosage of Ismelin. After control is established, the dosage of all drugs should be reduced to the lowest effective level.

Note: When Ismelin is replacing MAO inhibitors, at least 1 week should elapse before commencing treatment with Ismelin (see CONTRAINDICATIONS). If ganglionic blockers have not been discontinued before Ismelin is started, they should be gradually withdrawn to prevent a spiking blood pressure response during the transfer period.

HOW SUPPLIED

Tablets 10 mg – round, pale yellow, scored (imprinted CIBA 49)

Bottles of 100..................................................................................NDC 0083-0049-30

Tablets 25 mg – round, white, scored (imprinted CIBA 103)

Bottles of 100..................................................................................NDC 0083-0103-30

Do not store above 86°F (30°C).

Dispense in tight container (USP).

C96-14(Rev.3/96)

C I B A

Ciba-Geigy Corporation

Pharmaceuticals Division

Summit, New Jersey 07901

Ismelin  guanethidine monosulfate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0083-0049 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength guanethidine monosulfate (guanethidine) Active 10 MILLIGRAM  In 1 TABLET calcium stearate Inactive   colloidal silicon dioxide Inactive   D&C Yellow No. 10 Inactive   lactose Inactive   starch Inactive   stearic acid Inactive   sucrose Inactive

Product Characteristics Color YELLOW (pale yellow) Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code CIBA;49 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0083-0049-30 100 TABLET In 1 BOTTLE None

Ismelin  guanethidine monosulfate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0083-0103 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength guanethidine monosulfate (guanethidine) Active 25 MILLIGRAM  In 1 TABLET calcium stearate Inactive   colloidal silicon dioxide Inactive   lactose Inactive   starch Inactive   stearic acid Inactive   sucrose Inactive

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 10mm Flavor Imprint Code CIBA;103 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0083-0103-30 100 TABLET In 1 BOTTLE None

Revised: 08/2006Ciba-Geigy Corporation

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Japanese encephalitis virus vaccine Nakayama

Generic Name: Japanese encephalitis virus vaccine (Nakayama) (JAP a NEEZ en CEF a LYE tis NA ka YA ma)

Brand Names: Je-Vax

What is Japanese encephalitis virus vaccine (Nakayama)?

Japanese encephalitis is a serious disease caused by a virus. It is the leading cause of viral encephalitis (inflammation of the brain) in Asia. Encephalitis is an infection of the membrane around the brain and spinal cord. This infection often causes only mild symptoms, but prolonged swelling of the brain can cause permanent brain damage or death.

Japanese encephalitis virus is carried and spread by mosquitos.

The Japanese encephalitis Nakayama vaccine is used to help prevent this disease in adults and children who are at least 12 months old.

This vaccine works by exposing you to a small dose of the virus, which causes the body to develop immunity to the disease. This vaccine will not treat an active infection that has already developed in the body.

This vaccine is recommended for people who plan to spend 30 days or longer in areas where Japanese encephalitis is known to exist, or where an epidemic has recently occurred. The vaccine should also be given to people who will spend any amount of time in rural areas where Japanese encephalitis is endemic, or those who are otherwise at high risk of coming into contact with the virus.

You should receive this vaccine and all booster shots at least 10 days prior to your arrival in an area where you may be exposed to the virus.

Not everyone who travels to Asia needs to receive a Japanese encephalitis vaccine. Follow your doctor instructions or the recommendations of the Centers for Disease Control and Prevention (CDC).

This vaccine is also recommended for people who work in a research laboratory and may be exposed to Japanese encephalitis virus through needle-stick accidents or inhalation of viral droplets in the air.

Like any vaccine, the Japanese encephalitis Nakayama vaccine may not provide protection from disease in every person.

What is the most important information I should know about this vaccine?

The Japanese encephalitis Nakayama vaccine is given in a series of 3 shots. The booster shots are usually given 7 days and 2 weeks to 1 month after the first shot. Your individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Japanese encephalitis Nakayama vaccine is for use in adults and children who are at least 12 months old.

This vaccine is recommended for people who plan to spend 30 days or longer in areas where Japanese encephalitis is known to exist, or where an epidemic has recently occurred. The vaccine should also be given to people who will spend any amount of time in rural areas where Japanese encephalitis is endemic, or those who are otherwise at high risk of coming into contact with the virus.

You should receive the vaccine and all booster doses at least 10 days prior to your arrival in an area where you may be exposed to the virus.

Not everyone who travels to Asia needs to receive a Japanese encephalitis vaccine. Follow your doctor instructions or the recommendations of the Centers for Disease Control and Prevention (CDC).

This vaccine is also recommended for people who work in a research laboratory and may be exposed to Japanese encephalitis virus through needle-stick accidents or inhalation of viral droplets in the air.

Becoming infected with Japanese encephalitis is much more dangerous to your health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

What should I discuss with my healthcare provider before receiving this vaccine?

You should not receive this vaccine if you have ever had a life-threatening allergic reaction to a Japanese encephalitis vaccine, or if you are allergic to mouse proteins or a preservative called thimerosal. You should also not receive this vaccine if you have received cancer chemotherapy or radiation treatment in the past 3 months.

Before receiving this vaccine, tell the doctor if you are allergic to any foods or drugs, or if you have:

• 
  

  an allergy to insect (such as bee or wasp) stings;

  
  


• 
  

  a history of seizures;

  
  


• 
  

  a neurologic disorder or disease affecting the brain (or if this was a reaction to a previous vaccine); or

  
  


• 
  

  a weak immune system caused by disease, bone marrow transplant, or by using certain medicines or receiving cancer treatments.

  
  

You can still receive a vaccine if you have a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

Vaccines may be harmful to an unborn baby and generally should not be given to a pregnant woman. However, not vaccinating the mother could be more harmful to the baby if the mother becomes infected with a disease that this vaccine could prevent. Your doctor will decide whether you should receive this vaccine, especially if you have a high risk of infection with the Japanese encephalitis virus. Do not receive this vaccine without telling your doctor if you are breast-feeding a baby.

How is this vaccine given?

This vaccine is given as an injection (shot) under the skin. You will receive this injection in a doctor's office or other clinic setting.

The Japanese encephalitis Nakayama vaccine is given in a series of 3 shots. The booster shots are usually given 7 days and 2 weeks to 1 month after the first shot. Your individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Your care providers may want to watch you for signs of allergic reaction for at least 30 minutes after you receive this vaccine.

In addition to receiving the Japanese encephalitis vaccine, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could infect you with the Japanese encephalitis virus.

For at least 10 days after receiving a Japanese encephalitis vaccine, be sure to stay in an area where you have access to medical care in case of a delayed allergic reaction.

Your doctor may recommend treating fever and pain with an aspirin-free pain reliever such as acetaminophen (Tylenol) or ibuprofen (Motrin, Advil, and others) when the shot is given and for the next 24 hours. Follow the label directions or your doctor's instructions about how much of this medicine to take.

It is especially important to prevent fever from occurring if you have a seizure disorder such as epilepsy.

What happens if I miss a dose?

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure you receive all recommended doses of this vaccine. If you do not receive the full series of vaccines, you may not be fully protected against the disease.

What happens if I overdose?

An overdose of this vaccine is unlikely to occur.

What should I avoid before or after receiving this vaccine?

Avoid drinking large amounts of alcohol for at least 48 hours after you receive a Japanese encephalitis vaccine.

This vaccine side effects

You should not receive a booster vaccine if you had a life-threatening allergic reaction after the first shot. Keep track of any and all side effects you have after receiving this vaccine. When you receive a booster dose, you will need to tell the doctor if the previous shots caused any side effects.

Becoming infected with Japanese encephalitis is much more dangerous to your health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

Get emergency medical help if you have any of these signs of an allergic reaction (which may occur up to 17 days after you receive the shot): hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

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  feeling light-headed, fainting;

  
  


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  high fever;

  
  


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  behavior changes; or

  
  


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  seizures (black-out or convulsions).

  
  

Less serious side include:

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  redness, pain, or swelling where the shot was given;

  
  


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  low fever, chills, flu symptoms;

  
  


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  headache, tired feeling;

  
  


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  muscle pain;

  
  


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  nausea, vomiting, stomach pain; or

  
  


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  mild itching or skin rash.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Japanese encephalitis virus vaccine Dosing Information

Usual Adult Dose for Japanese Encephalitis Virus Prophylaxis:

1 mL subcutaneously on days 0, 7, and 30.
If there are time constraints, three doses may be given on days 0, 7, and 14.
If neither schedule can be followed, two doses given on days 0 and 7 will induce antibodies in up to 80% of recipients; however, this regimen is not recommended.
A booster dose of 1 mL may be given after 2 years. There are no data on optimal spacing of boosters after 2 years.

Available supplies are limited; use is restricted for children 1 to 16 years of age.

No information is available concerning the interchangeability of vaccines; however, because the supply of Japanese encephalitis virus vaccine Nakayama (Je-Vax) is limited, adults 17 years of age or older who require a booster dose may receive a 2 dose primary series of Japanese encephalitis virus vaccine SA14-14-2 (Ixiaro) when Je-Vax is not available and further vaccination is required.

Usual Pediatric Dose for Japanese Encephalitis Virus Prophylaxis:

1 year to 2 years: 0.5 mL subcutaneously on days 0, 7, and 30. A booster dose of 0.5 mL may be given after 2 years.
3 years or older: 1 mL subcutaneously on days 0, 7, and 30.

An abbreviated schedule with the third dose administered on day 14 should be used only when time does not permit waiting; 2 doses a week apart produce immunity in about 80% of recipients; the longest regimen yields highest titers after 6 months.


A booster dose of 1 mL may be given after 2 years. There are no data on optimal spacing of boosters after 2 years.

What other drugs will affect Japanese encephalitis virus vaccine (Nakayama)?

Before receiving this vaccine, tell the doctor about all other vaccines you have recently received.

Also tell the doctor if you have recently received drugs or treatments that can weaken the immune system, including:

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  an oral, nasal, inhaled, or injectable steroid medicine;

  
  


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  medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), efalizumab (Raptiva), etanercept (Enbrel), leflunomide (Arava), and others; or

  
  


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  medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

  
  

This list is not complete and there may be other drugs that can interact with Japanese encephalitis vaccine. Tell your doctor about all the prescription and over-the-counter medications you have received. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Japanese encephalitis virus vaccine resources

• Japanese encephalitis virus vaccine Use in Pregnancy & Breastfeeding
• Japanese encephalitis virus vaccine Drug Interactions
• Japanese encephalitis virus vaccine Support Group
• 0 Reviews for Japanese encephalitis virus vaccine - Add your own review/rating

• Je-Vax Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Japanese encephalitis virus vaccine with other medications

• Japanese Encephalitis Virus Prophylaxis

Where can I get more information?

• Your doctor or pharmacist may have information about this vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.