Totect

dexrazoxane hydrochloride

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Totect

Totect® is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

Totect Dosage and Administration

Vial contents must be mixed and diluted before use.

Recommended Dose

Totect® should be given once daily for 3 consecutive days. The first infusion should be initiated as soon as possible and within the first six hours after extravasation.

The individual dosage is based on calculation of the Body Surface Area (BSA) up to a maximum dose of 2000 mg (each on Day 1 and 2) and 1000 mg (Day 3), corresponding to a BSA of 2 m2.

The recommended dose is:	Maximum daily dose:
Day one: 1000 mg/m2	2000 mg
Day two: 1000 mg/m2	2000 mg
Day three: 500 mg/m2	1000 mg

Dose Modifications

The Totect® dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min.

Directions for Mixing and Final Dilution

Read this entire section carefully before mixing and diluting.

Aseptic technique should be used during preparation.

Caution must be exercised when handling Totect® and preparing the mixed solution. [see How Supplied/Storage and Handling (16)]

Totect® should not be mixed or administered with any other drug during the infusion.

Preparation of Totect®

Step 1. Each vial of Totect® (dexrazoxane for injection) (500 mg) must first be mixed with 50 mL of the enclosed diluent. The resultant solution contains 10 mg/mL. This resultant solution should be used immediately (within 2 hours) after preparation. It contains no antibacterial preservative.

Step 2. Withdraw the recommended dose from the solution containing 10 mg/mL as prepared in Step 1 and further dilute into an infusion bag containing 1000 mL 0.9% Sodium Chloride. In order to obtain the required dose more than one vial may be needed. Totect® must not be mixed with any other drugs.

The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when stored below 25ºC (77ºF).

The solution of Totect® is slightly yellow.

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. Vials are for single use only. Unused solution should be discarded.

Administration

Totect® should not be mixed or administered with any other drug during the infusion. Administer as an intravenous infusion over 1 to 2 hours at room temperature and normal light conditions in a large caliber vein in an extremity/area other than the one affected by the extravasation. Cooling procedures such as ice packs, if used, should be removed from the extravasation area at least 15 minutes before Totect® administration in order to allow sufficient blood flow to the area of extravasation. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day.

Dosage Forms and Strengths

Totect® is packaged as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

Contraindications

None.

Warnings and Precautions

Myelosuppression

Treatment with Totect® is associated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed.

Use in Pregnancy

Pregnancy Category D

Totect® can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect® in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [see Use in Special Populations (8.1)].

Adverse Reactions

Clinical Trials Experience

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

In the clinical studies, Totect® was administered to patients also receiving chemotherapeutic agents for cancer, and the adverse reaction profile reflects the combination of Totect®, underlying disease, and already administered chemotherapy. The adverse reaction data reflect exposure to Totect® in 80 patients who received the first dose, 72 patients who received two doses, and 69 patients who received all three doses. Table 1 summarizes adverse reactions occurring with ≥ 5% frequency.

Table 1 Adverse Reactions Occurring at ≥ 5% Frequency

MedDRA System Organ Class (SOC) and Preferred term	Study 1 and 2 Combined (All causalities) N=80 (%)
Total number of patients with at least one event	68 (85)
General disorders and administration site conditions	46 (58)
Pyrexia	17 (21)
Injection site pain/injection site discomfort	13 (16)
Fatigue	10 (13)
Edema peripheral	8 (10)
Injection site phlebitis	5 (6)
Gastrointestinal disorders	44 (55)
Nausea	34 (43)
Vomiting	15 (19)
Diarrhea	9 (11)
Abdominal pain	5 (6)
Constipation	5 (6)
Infections and infestations	24 (30)
Postoperative infection	13 (16)
Nervous system disorders	19 (24)
Dizziness	9 (11)
Headache	5 (6)
Skin and subcutaneous disorders	14 (18)
Alopecia	11 (14)
Respiratory, thoracic and mediastinal disorders	13 (16)
Dyspnea	6 (8)
Pneumonia     Cough	5 (6) 4 (5)
Vascular disorders	12 (15)
Blood and lymphatic system disorders	11 (14)
Anemia	5 (6)
Psychiatric disorders	11 (14)
Depression     Insomnia	6 (8) 4 (5)
Musculoskeletal and connective tissue disorders	10 (13)
Metabolism and nutrition disorders     Anorexia	8 (10) 4 (5)
Cardiac disorders	4 (5)

Neutropenia and febrile neutropenia each occurred in 2.5% of patients.

Table 2 summarizes laboratory adverse events from studies 1 and 2.

Table 2: Laboratory Adverse Reactions

CTCAE version 3 Term	CTC grade 3	CTC grade 4	CTC grade 2 to 4
	N (%)	N (%)	N (%)
Hematologic:
Decreased hemoglobin	2 (3)	0	34 (43)
Decreased WBC	20 (25)	16 (20)	58 (73)
Decreased neutrophils	17 (22)	19 (24)	48 (61)
Decreased platelets	17 (21)	0	21 (26)
Hepatic:
Increased bilirubin	1 (2)	0	6 (11)
Increased AST	1 (1)	1 (1)	21 (28)
Increased ALT	1 (1)	4 (5)	17 (22)
Increased alkaline phosphatase	0	0	3 (4)
Increased LDH	0	0	1 (5)
Metabolic:
Increased creatinine	1 (2)	1 (2)	8 (14)
Decreased sodium	4 (5)	1 (1)	5 (6)
Increased calcium total	1 (2)	1 (2)	4 (7)

Drug Interactions

No drug interactions have been identified [see Clinical Pharmacology (12.3)].

• 
  

  Dimethylsulfoxide: Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect®. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane.

  
  

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.2)].

Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on an mg/m2 basis) and embryotoxic and teratogenic at 8 mg/kg (about 1/20 the human dose on an mg/m2 basis) when given daily during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg (about 1/16 the human dose on an mg/m2 basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/4 the human dose on an mg/m2 basis) were embryotoxic and teratogenic. Teratogenic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of Totect® in pediatric patients have not been established.

Geriatric Use

In total, 21% of the patients treated with Totect® were age 65 years or older and 9% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.2)].

Renal Impairment

Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect® dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min. [see Dosage and Administration (2.2)]

Overdosage

There are no data on overdosage. There is no known antidote for dexrazoxane.

Totect Description

Totect® (dexrazoxane for injection) is a sterile, pyrogen-free lyophilizate intended for intravenous (IV) administration. Totect® is packaged as a kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

Chemically, dexrazoxane is 2,6-piperazinedione,4,4'-(1-methyl-1,2-ethanediyl)bis-,(S)- or (S)-(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane. The following diagram shows the chemical structure:

The molecular formula is C11H16N4O4; the molecular weight is 268.3. Dexrazoxane is a white to off-white powder, with a melting point of 194 ± 3 °C. It is soluble in dioxane and 0.1 N HCl, sparingly soluble in water, tetrahydrofuran, citrate buffer at pH 4.0, phosphate buffer at pH 7.0, and borate-potassium chloride sodium hydroxide buffer at pH 9.0. The acid dissociation constants, pKa, are 2.5 (for the tertiary piperazine nitrogen) and 9.7 (for the nitrogen imide). Log P is -2.135.

The finished product is supplied in a sterile form for intravenous infusion only following mixing and diluting.

Each kit contains twenty 50 mL Type I glass vials. Ten vials each contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane and 10 vials each contains diluent (0.167M Sodium Lactate Injection, USP). Each vial of dexrazoxane for injection is closed with an aluminum flip-off cap covered with a dark red overcap. Each vial of diluent is closed with an aluminum flip-off cap covered with a white overcap.

When reconstituted as directed, the admixture contains dexrazoxane and the following excipients: hydrochloric acid, sodium lactate, water for injection, sodium hydroxide and lactic acid [see Dosage and Administration (2.4)]. The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.

Totect - Clinical Pharmacology

Mechanism of Action

The mechanism by which Totect® diminishes tissue damage resulting from the extravasation of anthracycline drugs is unknown. Some evidence suggests that dexrazoxane inhibits topoisomerase II reversibly.

Pharmacokinetics

The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, the pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose-range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 μg/mL at the end of the 15 minute infusion of a 500 mg/m2 dose of dexrazoxane administered 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in the following table.

SUMMARY OF MEAN (%CVa) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT A DOSAGE RATIO OF 10:1 OF DEXRAZOXANE: DOXORUBICIN

a Coefficient of variation
b Steady-state volume of distribution
Dose Doxorubicin (mg/m2)	Dose Dexrazoxane (mg/m2)	Number of Subjects	Elimination Half-Life (h)	Plasma Clearance (L/h/m2)	Renal Clearance (L/h/m2)	bVolume of Distribution (L/m2)
50	500	10	2.5 (16)	7.88 (18)	3.35 (36)	22.4 (22)
60	600	5	2.1 (29)	6.25 (31)	—	22.0 (55)

Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours. The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/m2).

In a study of the pharmacokinetics of dexrazoxane following the recommended dosing for patients with anthracycline extravasation, the mean systemic clearance and steady-state volume of distribution of dexrazoxane in six female patients undergoing treatment for anthracycline extravasations at a dose of 1000 mg/m2 Totect® on Days 1 and 2 and 500 mg/m2 on Day 3 were similar to that observed when administered with doxorubicin. The systemic clearances (mean ± SD) were similar among Day 1 (5.9 ± 2.0 L/h/m2), Day 2 (6.4 ± 2.1 L/h/m2), and Day 3 (7.9 ± 3.0 L/h/m2). The terminal elimination half life did not change over 3 days (2.1-2.2 h). The volume of distribution was 17.9 ~ 22.6 L/m2.

Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies.

Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.

Protein Binding: In vitro studies have shown that dexrazoxane is not bound to plasma proteins.

Effects of Gender

There are no clinically relevant differences in the pharmacokinetics of dexrazoxane between males and females.

Renal insufficiency

The pharmacokinetics of dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/m2 of dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CLCR) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was twofold greater in subjects with moderate (CLCR 30-50 mL/min) to severe (CLCR < 30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values < 40 mL/min compared with control subjects (CLCR > 80 mL/min) [see Dosage and Administration (2.2)].

Hepatic insufficiency

The pharmacokinetics of dexrazoxane have not been evaluated in patients with hepatic impairment.

Drug interactions

There were no significant changes in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2) in a crossover study in cancer patients.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic.

The possible adverse effects of Totect® on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

Clinical Studies

Totect® was studied in two open-label, single arm, multi-center studies testing whether Totect® administration could reduce tissue injury following anthracycline extravasation and thereby reduce or avoid surgical intervention.

In the studies, eligible patients were receiving single-agent anthracycline intravenously (usually as part of combination chemotherapy) and developed extravasation symptoms of pain, burning, swelling, and/or redness near the infusion site. Skin biopsy samples from the suspected skin area were examined for the presence of anthracycline as determined by the presence of tissue fluorescence; however, therapy was not delayed for this test result.

In both studies, treatment with Totect® was to begin as soon as possible and no later than 6 hours after extravasation with retreatment 24 and 48 hours later (a total of 3 doses). Totect® was administered as 1-2 hour IV infusions through a different venous access location. The first and second doses were 1000 mg/m2 and the third dose was 500 mg/m2. No dose modifications were planned except for patients whose body surface area exceeded 2.0 m2, in which case the total daily dose limit on the first and second day was 2000 mg/day and 1000 mg on the third day.

In total, 80 patients were enrolled and 57 were evaluable. Demographics in the two studies were similar. The median age was 57 years, and sixty-five percent of patients were women. The anthracyclines most commonly associated with extravasation were epirubicin (56%) and doxorubicin (41%). Peripheral IV sites of extravasation included the forearm in 63%, the hand in 21%, and the antecubital area in 11%; four patients (5%) received the anthracycline via a central venous access device (CVAD). Most patients presented with swelling (83%), redness (78%), and pain (43%). The median baseline lesion area was 25 cm2 (range 1-253 cm2).

Evaluable patients had to be receiving IV anthracycline (single agent or in combination) at the time of extravasation, to have skin biopsies showing fluorescence, and to receive the first Totect® dose within 6 hours of the extravasation.

In study 1, none of the 19 evaluable patients required surgical intervention and none had serious late sequelae. In study 2, one of the 38 evaluable patients required surgery. One additional non-evaluable patient required surgery for tissue necrosis. Thirteen patients had late sequelae at the event site such as site pain, fibrosis, atrophy, and local sensory disturbance; all were judged as mild except in the one patient who required surgery. None of the 4 patients with CVADs required surgical intervention.

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.


2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html


3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.


4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society

How Supplied/Storage and Handling

Totect® is available as an urgent treatment kit for single patient use. Each kit contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

NDC 38423-110-01

Store at 25ºC (77ºF); excursions permitted between 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Protect from light. Keep vials in carton until ready for use.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 Direct contact of Totect® with the skin or mucous membrances prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water.

Rx Only

Patient Counseling Information

See FDA-approved Patient Labeling (17.3)

Myelosuppression

Treatment with Totect® is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring. [see Warnings and Precautions (5.1)]

Pregnancy

Women who have potential to become pregnant should be advised that Totect® might cause fetal harm. [see Warnings and Precautions (5.3)]

FDA-Approved Patient Labeling

PATIENT INFORMATION

Totect®

(dex-ra-ZOX-ane)

(dexrazoxane)

Injection

Read the Patient Information that comes with Totect® before you receive treatment. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Totect®?

Totect® is a prescription medicine used to treat people when anthracycline chemotherapy leaks from your vein into the tissue around the intravenous (IV) site.

Totect® has not been studied in children.

What should I tell my healthcare provider before receiving Totect®?

Before receiving Totect®:

-

tell your healthcare provider about all your medical conditions including if you have any kidney problems.

-

tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, herbal or dietary supplements. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

-

tell your healthcare provider if you use a topical dimethylsulfoxide (DMSO). Topical DMSO should not be used in combination with Totect® since it may lessen the effect of Totect®.

-

tell your healthcare provider if you are pregnant, could be pregnant, or are planning to become pregnant, or are breast-feeding.


It is not known if Totect® passes into your breast milk. You and your doctor should decide if you will receive Totect® or breast feed. You should not do both. Talk to your doctor about the best way to feed your baby if you take Totect®. Do not breast feed while taking Totect®.

How will I receive Totect®?

-

Totect® is given to you in your healthcare provider's office, clinic or hospital.

-

Totect® is infused into a vein for 1 to 2 hours each day for three days.

What are the possible side effects of Totect®?

Totect® can cause serious side effects including:

• a decrease in white blood cell counts (leukopenia and neutropenia)


• a decrease in the blood cells which help your blood to clot (thrombocytopenia)

Blood tests may be needed to monitor for these side effects.

Common side effects:

• nausea


• fever


• pain at the intravenous site


• vomiting

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all the possible side effects of Totect®. For more information, ask your healthcare provider or pharmacist.

Talk to your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088 (1-800-332-1088) or at www.fda.gov/medwatch.

General Information about Totect®

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet.

This Patient Information summarizes the most important information about Totect®. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Totect® that is written for health professionals.

For more information, go to www.Totect.com or call 1-866-914-2922.

What are the ingredients in Totect®?

Active ingredient: dexrazoxane

Inactive ingredients: hydrochloric acid, sodium lactate, water for injection, sodium hydroxide and lactic acid

Marketed by:

Topotarget USA Inc.

100 Enterprise Drive

Rockaway, New Jersey 07866

USA

Distributed and Packaged by:

Integrated Commercialization Solutions

Brooks, KY 40109

USA

See www.Totect.com webpage for the distributors

Manufactured by:

Ben Venue Laboratories, Inc.

Bedford, Ohio 44146

USA

Hameln Pharmaceuticals GmbH

31789 Hameln

Germany

Manufactured for:

Topotarget A/S

Symbion Science Park

Fruebjergvej 3

DK-2100 Copenhagen

Denmark

Totect® is a registered trademark of Topotarget A/S, Copenhagen, Denmark.

US Patent No 6,727,253 B2

May 2011

TOT-PIL/v05

BOX LABEL – PRINCIPAL DISPLAY PANEL

NDC 38423-110-01

Topotarget logo

Totect®

(dexrazoxane) for injection

500 mg

Sterile product

For Intravenous Use Following Reconstitution and Dilution Only

Vials are for single use only. Unused solution should be discarded.

After mixing with 50 mL Diluent for Totect® 1 mL contains 10 mg dexrazoxane.

See package insert for information on dosage and preparation for use.

KIT FOR ANTHRACYCLINE EXTRAVASATION

Each Totect® vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane. Each vial of Diluent for Totect® contains Sodium lactate 50% 1.87 g, Lactic Acid q.s., Sodium hydroxide q.s., Water for injection q.s. ad 50 mL.

Totect  dexrazoxane  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 38423-110

Packaging # NDC Package Description Multilevel Packaging 1 38423-110-01 1 KIT In 1 BOX None

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 10 VIAL, SINGLE-USE   10  Part 2 10 VIAL, SINGLE-USE   10

Part 1 of 2 Totect  dexrazoxane hydrochloride  injection, powder, lyophilized, for solution

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength dexrazoxane hydrochloride (dexrazoxane) dexrazoxane hydrochloride 500 mg

Inactive Ingredients Ingredient Name Strength hydrochloric acid

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 1 VIAL In 1 VIAL, SINGLE-USE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022025 10/16/2007

Part 2 of 2 SODIUM LACTATE  sodium lactate  injection, solution, concentrate

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sodium Lactate (sodium cation) Sodium Lactate 50 mL

Inactive Ingredients Ingredient Name Strength lactic acid   sodium hydroxide   water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 1 VIAL In 1 VIAL, SINGLE-USE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022025 10/16/2007

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date

Petidina Clorhidrato

Petidina Clorhidrato may be available in the countries listed below.

Ingredient matches for Petidina Clorhidrato

Pethidine

Pethidine hydrochloride (a derivative of Pethidine) is reported as an ingredient of Petidina Clorhidrato in the following countries:

• Chile

International Drug Name Search

Clozapine A

Clozapine A may be available in the countries listed below.

Ingredient matches for Clozapine A

Clozapine

Clozapine is reported as an ingredient of Clozapine A in the following countries:

• Netherlands

International Drug Name Search

Clazic SR

Clazic SR may be available in the countries listed below.

Ingredient matches for Clazic SR

Gliclazide

Gliclazide is reported as an ingredient of Clazic SR in the following countries:

• Vietnam

International Drug Name Search

Hedix

Hedix may be available in the countries listed below.

Ingredient matches for Hedix

Diazepam

Diazepam is reported as an ingredient of Hedix in the following countries:

• Indonesia

Metamizole

Metamizole is reported as an ingredient of Hedix in the following countries:

• Indonesia

International Drug Name Search

SANDIMMUN Concentrate for Solution for infusion 50mg / ml

SANDIMMUN

Concentrate for Solution for Infusion 50 mg/ml

(ciclosporin)

This product will be called Sandimmun in this leaflet.

What you need to know about Sandimmun

Your doctor has decided that you need this medicine to help treat your condition.

Please read this leaflet carefully before you start your treatment. It contains important information. Keep the leaflet in a safe place because you may want to read it again.

If you have any other questions, or if there is something you don’t understand, please ask your doctor or pharmacist.

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

In this leaflet:

• 1. What Sandimmun is and what it’s used for


• 2. Things to consider before you have Sandimmun


• 3. Administering Sandimmun


• 4. Possible side effects


• 5. How to store Sandimmun


• 6. Further information

What Sandimmun is and what it’s used for

Sandimmun is a clear, brown/yellow oily liquid containing 50 mg/ml of the active ingredient, ciclosporin. It is used to prepare a solution which is administered by intravenous infusion.

Ciclosporin is one of a group of drugs known as immunosuppressive agents. These drugs are used to dampen down the body's immune reactions.

Sandimmun can be used to prevent rejection after a kidney, liver, heart, heart/lung, lung, pancreas or bone marrow transplant.

Although you may have had a series of tests before your organ or bone marrow transplant to ensure that the match between your body and the transplanted organ or bone marrow is as close as possible, the donor tissue will still not be identical to your tissue. As a result, your body's immune system will try to reject the donor tissue. Sandimmun helps to stop this rejection response by blocking the development of special cells which would normally attack the transplanted tissue.

Things to consider before you have Sandimmun

Some people MUST NOT have Sandimmun. Talk to your doctor if:

• you think you may be allergic to ciclosporin, or to any of the other ingredients of Sandimmun. (These are listed at the end of the leaflet.)


• You are taking a drug called tacrolimus.


• You are taking a drug called rosuvastatin.


• You are breastfeeding.

You should also ask yourself these questions before having Sandimmun. If the answer to any of these questions is YES, discuss your treatment with the doctor or nurse because Sandimmun might not be the right medicine for you.

• Have you previously had an injection or infusion containing polyethoxylated castor oil (see Important information about some of the ingredients of Sandimmun, below)?


• Are you allergic to many things?


• Have you been told that you have high levels of potassium in your blood? Are you taking potassium supplements or is your diet particularly rich in potassium? (Fruit and vegetables are rich sources of potassium.)


• Do you have gout or other conditions caused by high levels of uric acid in your blood?


• Are you worried about any unusual spots, moles or warts on your skin?


• Are you out in the sun a lot, or do you use a sun bed?


• Do you have any skin infections, including herpes (cold sores)?


• Are you pregnant?

Are you taking other medicines?

Ciclosporin interacts with a large number of other medicines and this can interfere with your treatment. Tell your doctor or nurse if you are taking any of the following:

• Medicines to treat heart problems or high blood pressure such as bosentan, diltiazem, nicardipine and verapamil.


• Drugs containing potassium (your doctor will know which these are).


• Medicines called NSAIDs used to treat pain and inflammation. (Some of these can be bought over-the-counter).


• Medicines to treat infections including antibiotics (especially erythromycin and clarithromycin) and antifungal medicines (especially terbinafine and voriconazole).


• Oral contraceptives.


• Medicines for epilepsy.


• Cholesterol lowering medicines (including statins).


• Sleeping tablets.


• Potassium supplements.


• Diuretics or “water tablets” that affect the amount of urine you produce and might also affect the level of potassium in your blood.


• Danazol (used to treat menstrual disorders, endometriosis or breast problems).


• St John’s Wort: The herbal remedy St John’s Wort (Hypericum perforatum) should not be taken at the same time as this medicine. If you are already taking St John’s Wort consult your doctor before stopping the St John’s Wort preparation.


• Octreotide (known as Sandostatin).


• Medicines to treat tuberculosis.


• Medicines to treat gout.


• Metoclopramide (used to stop sickness).


• Melphalan (used to treat lymphomas or tumours).


• Imatinib (used to treat leukaemia or tumours).


• Orlistat (used to help weight loss).


• Ticlopidine (used after a stroke).


• Corticosteroids (used to treat conditions such as asthma, allergic conditions, inflammatory
  conditions including inflammatory bowel disease, adrenocortical insufficiency and rheumatic disease).


• Ursodeoxycholic acid (used to treat gallstones).


• Protease inhibitors (used to treat Human Immunodeficiency Virus (HIV)).


• Tacrolimus, sirolimus and everolimus (other immunosuppressants).


• Methotrexate (used to treat tumours, severe psoriasis and rheumatoid arthritis).


• Etoposide (used to treat cancer).


• Repaglinide (used to treat diabetes).

Always tell your doctor or pharmacist about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor.

Will there be any problems with driving or using machinery?

Not applicable.

Other special warnings

• Ciclosporin can affect how the liver and kidneys work. It can also affect blood pressure, and the composition of the blood. Your doctor will monitor you closely while you are being treated.


• Because ciclosporin dampens down the immune system you are more prone to catch infections and they can become very serious. If you experience vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and muscle weakness, these can be the signs and symptoms of an infection of the brain called progressive multifocal leukoencephalopathy. Make sure your doctor or nurse knows if you are feeling unwell.


• There have been very rare reports of people developing a condition called Benign Intracranial Hypertension when they are being treated with ciclosporin. Tell your doctor as soon as possible if you start to feel nauseous, develop tinnitus (ringing in your ears), or get pains in your head, neck or back, or problems with your sight, balance or memory.


• You must not eat a fatty meal or grapefruit, or drink grapefruit juice, before your infusion.


• If you have recently had a vaccination or are planning to have any vaccinations make sure the doctor or nurse knows you are being treated with Sandimmun.


• You must visit the dentist regularly while you are being treated with Sandimmun to make sure that your gums remain healthy.

Important information about some of the ingredients of Sandimmun

Sandimmun contains:

• Polyethoxylated castor oil which may cause severe allergic reactions.


• 34.4% ethanol (alcohol). A 100mg dose of Sandimmun contains 556 mg of ethanol equivalent to nearly three teaspoons of beer or one teaspoon of wine. This may be harmful if you are suffering from alcoholism and should be taken into account if you are pregnant or breast feeding, have liver disease, epilepsy or if this medicine is being given to a child.

Administering Sandimmun

Your doctor will work out the correct dose of Sandimmun for you depending on your body weight and your condition.

The usual dose is from 3 to 5 mg/kg body weight per day starting on the day before your transplant operation and continuing for up to two weeks after the operation. You will be started on oral ciclosporin (capsules or liquid) as soon as possible after the operation.

You will be given Sandimmun by slow intravenous infusion over a period of 2 to 6 hours. Sandimmun will be diluted with normal saline or 5% glucose before use.

If you think you have been given too much tell the doctor or nurse as soon as possible.

Possible side effects

Most people who are treated with Sandimmun benefit. Like all medicines though, it can sometimes cause side effects in some people.

If you develop a sore throat, any infections, or begin to feel generally unwell, tell the doctor or nurse immediately.

The following side effects have been reported:

More than 10% of people have experienced:

Kidney problems, high blood pressure, headache, tremor and increased levels of lipids (for example cholesterol) in the blood.

Up to 1 in 10 people have experienced:

Numbness or tingling, loss of appetite, feeling or being sick, stomach pain, diarrhoea, swollen gums, liver problems, high level of uric acid or potassium in the blood, low levels of magnesium in the blood, muscle pain or cramp, increased hair growth on the body and tiredness.

Up to 1 in 100 people have experienced:

Seizures, confusion, disorientation, decreased responsiveness, agitation, sleeplessness, visual disturbances, blindness, coma, partial paralysis, loss of co-ordination, changes in blood (for example anaemia), allergic rash, water retention which may cause swelling and weight increase.

Up to 1 in 1,000 people have experienced:

Problems with the nerves that control muscles, inflammation of the pancreas, high levels of glucose in the blood, muscle weakness, wasting of muscles, destruction of red blood cells which may be associated with kidney problems, changes in the menstrual cycle in women and slight enlarging of the breasts in men.

Up to 1 in 10,000 people have experienced:

Swelling at the back of the eye which may be associated with an increase in pressure inside the head (benign intracranial hypertension) and visual disturbances.

Like other medicines that dampen down the immune system, ciclosporin may cause tumours or other malignancies, particularly of the skin. It may also make you more likely to get infections which may be serious. If you experience vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and muscle weakness, these can be the signs and symptoms of an infection of the brain called progressive multifocal leukoencephalopathy.

Tell your doctor or pharmacist if you suffer from any of these effects, or from any other side effects not mentioned in this leaflet.

How to store Sandimmun

Keep out of the reach and sight of children.

Store below 30°C.

Do not use Sandimmun after the expiry date which is printed on the outside of the pack.

Further information

SANDIMMUN Concentrate for Solution for Infusion is a clear, brown-yellow, oily liquid containing 50 mg ciclosporin per ml. It also contains the inactive ingredients absolute ethanol and polyethoxylated castor oil.

SANDIMMUN Concentrate for Solution for Infusion is available in 1 ml and 5 ml ampoules. Some of these pack sizes may not be marketed.

The product licence holder is

Novartis Pharmaceuticals UK Limited

trading as Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

Released onto the market by

Novartis Pharmaceuticals UK Limited

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

England

This leaflet was revised in November 2009.

If you would like any more information, or would like the leaflet in a different format, please contact Medical Information at Novartis Pharmaceuticals UK Ltd, telephone number 01276 698370.

SANDIMMUN is a registered trade mark

Copyright Novartis Pharmaceuticals UK Limited

Aggrastat Vial 250mcg / ml Concentrate for solution for Infusion

1. Name Of The Medicinal Product

AGGRASTAT^®*(250 micrograms/ml) Concentrate for solution for infusion

2. Qualitative And Quantitative Composition

1 ml of concentrate for solution for infusion contains 281 micrograms of tirofiban hydrochloride monohydrate which is equivalent to 250 micrograms tirofiban.

For excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

A clear, colourless concentrated solution.

4. Clinical Particulars

4.1 Therapeutic Indications

'Aggrastat' is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes.

Patients most likely to benefit from 'Aggrastat' treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (see also 4.2 'Posology and method of administration' and 5.1 'Pharmacodynamic properties').

'Aggrastat' is intended for use with acetylsalicylic acid and unfractionated heparin.

4.2 Posology And Method Of Administration

This product is for hospital use only, by specialist physicians experienced in the management of acute coronary syndromes.

'Aggrastat' concentrate for solution for infusion must be diluted before use.

'Aggrastat' is given intravenously at an initial infusion rate of 0.4 microgram/kg/min for 30 minutes. At the end of the initial infusion, 'Aggrastat' should be continued at a maintenance infusion rate of 0.1 microgram/kg/min. 'Aggrastat' should be given with unfractionated heparin (usually an intravenous bolus of 5,000 units [U] simultaneously with the start of 'Aggrastat' therapy, then approximately 1,000 U per hour, titrated on the basis of the activated thromboplastin time [APTT], which should be about twice the normal value) and ASA (see 5.1 'Pharmacodynamic properties', PRISM-PLUS study), unless contra-indicated.

No dosage adjustment is necessary for the elderly (see also 4.4 'Special warnings and special precautions for use').

Patients with severe kidney failure

In severe kidney failure (creatinine clearance <30 ml/min) the dosage of 'Aggrastat' should be reduced by 50% (see also 4.4 'Special warnings and precautions for use' and 5.2 'Pharmacokinetic properties').

The following table is provided as a guide to dosage adjustment by weight.

'Aggrastat' Concentrate for Solution for Infusion must be diluted to the same strength as 'Aggrastat' Injection Premixed, as noted under Instructions for Use.

	Most Patients	Severe Kidney Failure
Patient Weight (kg)	30 min Loading Infusion Rate (ml/hr)	Maintenance Infusion Rate (ml/hr)	30 min Loading Infusion Rate (ml/hr)	Maintenance Infusion Rate (ml/hr)
30-37	16	4	8	2
38-45	20	5	10	3
46-54	24	6	12	3
55-62	28	7	14	4
63-70	32	8	16	4
71-79	36	9	18	5
80-87	40	10	20	5
88-95	44	11	22	6
96-104	48	12	24	6
105-112	52	13	26	7
113-120	56	14	28	7
121-128	60	15	30	8
129-137	64	16	32	8
138-145	68	17	34	9
146-153	72	18	36	9

Start and duration of therapy with 'Aggrastat'

'Aggrastat' optimally should be initiated within 12 hours after the last anginal episode. The recommended duration should be at least 48 hours. Infusion of 'Aggrastat' and unfractionated heparin may be continued during coronary angiography and should be maintained for at least 12 hours and not more than 24 hours after angioplasty/atherectomy. Once a patient is clinically stable and no coronary intervention procedure is planned by the treating physician, the infusion should be discontinued. The entire duration of treatment should not exceed 108 hours.

Concurrent therapy (unfractionated heparin, ASA)

Treatment with unfractionated heparin is initiated with an i.v. bolus of 5,000 U and then continued with a maintenance infusion of 1,000 U per hour. The heparin dosage is titrated to maintain an APTT of approximately twice the normal value.

Unless contra-indicated, all patients should receive ASA orally before the start of 'Aggrastat' (see 5.1 'Pharmacodynamic properties', PRISM-PLUS study). This medication should be continued at least for the duration of the infusion of 'Aggrastat'.

If angioplasty (PTCA) is required, heparin should be stopped after PTCA, and the sheaths should be withdrawn once coagulation has returned to normal, e.g. when the activated clotting time (ACT) is less than 180 seconds (usually 2-6 hours after discontinuation of heparin).

Instructions for use

'Aggrastat' Concentrate must be diluted before use:

1. Draw 50 ml from a 250 ml container of sterile 0.9% saline or 5% glucose in water and replace with 50 ml 'Aggrastat' (from one 50 ml puncture vial) to make up a concentration of 50 microgram/ml. Mix well before use.

2. Use according to the dosage table above.

Where the solution and container permit, parenteral drugs should be inspected for visible particles or discoloration before use.

'Aggrastat' should only be given intravenously and may be administered with unfractionated heparin through the same infusion tube.

It is recommended that 'Aggrastat' be administered with a calibrated infusion set using sterile equipment.

Care should be taken to ensure that no prolongation of the infusion of the initial dose occurs and that miscalculation of the infusion rates for the maintenance dose on the basis of the patient's weight is avoided.

4.3 Contraindications

'Aggrastat' is contra-indicated in patients who are hypersensitive to the active substance or to any of the excipients of the preparation or who developed thrombocytopenia during earlier use of a GP IIb/IIIa receptor antagonist.

Since inhibition of platelet aggregation increases the bleeding risk, 'Aggrastat' is contra-indicated in patients with:

• History of stroke within 30 days or any history of haemorrhagic stroke.

• Known history of intracranial disease (e.g. neoplasm, arteriovenous malformation, aneurysm).

• Active or recent (within the previous 30 days of treatment) clinically relevant bleeding (e.g. gastro-intestinal bleeding).

• Malignant hypertension.

• Relevant trauma or major surgical intervention within the past six weeks.

• Thrombocytopenia (platelet count <100,000/mm³), disorders of platelet function.

• Clotting disturbances (e.g. prothrombin time>1.3 times normal or INR [International Normalised Ratio]>1.5).

• Severe liver failure.

4.4 Special Warnings And Precautions For Use

The administration of 'Aggrastat' alone without unfractionated heparin is not recommended.

There is limited experience with concomitant administration of 'Aggrastat' with enoxaparin (see also 5.1 'Pharmacodynamic properties' and 5.2 'Pharmacokinetic properties'). The concomitant administration of 'Aggrastat' with enoxaparin is associated with a higher frequency of cutaneous and oral bleeding events, but not in TIMI bleeds^**, when compared with the concomitant administration of 'Aggrastat' and unfractionated heparin. An increased risk of serious bleeding events associated with the concomitant administration of 'Aggrastat' and enoxaparin cannot be excluded, particularly in patients given additional unfractionated heparin in conjunction with angiography and/or PCI. The efficacy of 'Aggrastat' in combination with enoxaparin has not been established. The safety and efficacy of 'Aggrastat' with other low molecular weight heparins has not been investigated.

There is insufficient experience with the use of tirofiban hydrochloride in the following diseases and conditions, however, an increased risk of bleeding is suspected. Therefore, tirofiban hydrochloride is not recommended in:

• Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or lithotripsy within the past two weeks

• Severe trauma or major surgery>6 weeks but <3 months previously

• Active peptic ulcer within the past three months

• Uncontrolled hypertension (>180/110 mm Hg)

• Acute pericarditis

• Active or a known history of vasculitis

• Suspected aortic dissection

• Haemorrhagic retinopathy

• Occult blood in the stool or haematuria

• Thrombolytic therapy (see 4.5 'Interaction with other medicinal products and other forms of interaction').

• Concurrent use of drugs that increase the risk of bleeding to a relevant degree (see 4.5 'Interaction with other medicinal products and other forms of interaction').

There is no therapeutic experience with tirofiban hydrochloride in patients for whom thrombolytic therapy is indicated (e.g. acute transmural myocardial infarction with new pathological Q-waves or elevated ST-segments or left bundle-branch block in the ECG). Consequently, the use of tirofiban hydrochloride is not recommended in these circumstances.

'Aggrastat' infusion should be stopped immediately if circumstances arise that necessitate thrombolytic therapy (including acute occlusion during PTCA) or if the patient must undergo an emergency coronary artery bypass graft (CABG) operation or requires an intra-aortic balloon pump.

There are limited efficacy data in patients immediately undergoing PTCA.

There is no therapeutic experience with 'Aggrastat' in children, thus, the use of 'Aggrastat' is not recommended in these patients.

Other precautionary notes and measures

There are insufficient data regarding the re-administration of 'Aggrastat'.

Patients should be carefully monitored for bleeding during treatment with 'Aggrastat'. If treatment of haemorrhage is necessary, discontinuation of 'Aggrastat' should be considered (see also 4.9 'Overdose'). In cases of major or uncontrollable bleeding, tirofiban hydrochloride should be discontinued immediately.

'Aggrastat' should be used with special caution in the following conditions and patient groups:

• Recent clinically relevant bleeding (less than one year)

• Puncture of a non-compressible vessel within 24 hours before administration of 'Aggrastat'

• Recent epidural procedure (including lumbar puncture and spinal anaesthesia)

• Severe acute or chronic heart failure

• Cardiogenic shock

• Mild to moderate liver insufficiency

• Platelet count <150,000/mm³, known history of coagulopathy or platelet function disturbance or thrombocytopenia

• Haemoglobin concentration less than 11 g/dl or haematocrit <34%.

Special caution should be used during concurrent administration of, ticlopidine, clopidogrel, adenosine, dipyridamole, sulfinpyrazone, and prostacyclin.

Elderly patients, female patients, and patients with low body weight

Elderly and/or female patients had a higher incidence of bleeding complications than younger or male patients, respectively. Patients with a low body weight had a higher incidence of bleeding than patients with a higher body weight. For these reasons 'Aggrastat' should be used with caution in these patients and the heparin effect should be carefully monitored.

Impaired renal function

There is evidence from clinical studies that the risk of bleeding increases with decreasing creatinine clearance and hence also reduced plasma clearance of tirofiban. Patients with decreased renal function (creatinine clearance <60ml/min) should therefore be carefully monitored for bleeding during treatment with 'Aggrastat' and the heparin effect should be carefully monitored. In severe kidney failure the 'Aggrastat' dosage should be reduced (see also 4.2 'Posology and method of administration').

Femoral artery line

During treatment with 'Aggrastat' there is a significant increase in bleeding rates, especially in the femoral artery area, where the catheter sheath is introduced. Care should be taken to ensure that only the anterior wall of the femoral artery is punctured. Arterial sheaths may be removed when coagulation has returned to normal, e.g. when activated clotting time (ACT) is less than 180 seconds, (usually 2–6 hours after discontinuation of heparin).

After removal of the introducer sheath, careful haemostasis should be ensured under close observation.

General nursing care

The number of vascular punctures, and intramuscular injections should be minimised during the treatment with 'Aggrastat'. I.V. access should only be obtained at compressible sites of the body. All vascular puncture sites should be documented and closely monitored. The use of urinary catheters, nasotracheal intubation and nasogastric tubes should be critically considered.

Monitoring of laboratory values

Platelet count, haemoglobin and haematocrit levels should be determined before treatment with 'Aggrastat' as well as within 2-6 hours after start of therapy with 'Aggrastat' and at least once daily thereafter while on therapy (or more often if there is evidence of a marked decrease). In patients who have previously received GPIIb/IIIa receptor antagonists (cross reactivity can occur), the platelet count should be monitored immediately e.g. within the first hour of administration after re-exposure (see also 4.8 Undesirable effects). If the platelet count falls below 90,000/mm³, further platelet counts should be carried out in order to rule out pseudothrombocytopenia. If thrombocytopenia is confirmed, 'Aggrastat' and heparin should be discontinued. Patients should be monitored for bleeding and treated if necessary (see also 4.9 'Overdose').

In addition, activated thromboplastin time (APTT) should be determined before treatment and the anticoagulant effects of heparin should be carefully monitored by repeated determinations of APTT and the dose should be adjusted accordingly (see also 4.2 Posology and method of administration). Potentially life-threatening bleeding may occur especially when heparin is administered with other products affecting haemostasis, such as GPIIb/IIIa receptor antagonists.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The use of several platelet aggregation inhibitors increase the risk of bleeding, likewise their combination with heparin, warfarin and thrombolytics. Clinical and biological parameters of haemostasis should be regularly monitored.

The concomitant administration of 'Aggrastat' and ASA (acetylsalicyclic acid or aspirin) increases the inhibition of platelet aggregation to a greater extent than aspirin alone, as measured by ex vivo APD-induced platelet aggregation test. The concomitant administration of 'Aggrastat' and unfractionated heparin increases the prolongation of the bleeding time to a greater extent as compared to unfractionated heparin alone.

With the concurrent use of 'Aggrastat' and unfractionated heparin and ASA there was a higher incidence of bleeding than when only unfractionated heparin and ASA were used together (see also 4.4 'Special warnings and special precautions for use' and 4.8 'Undesirable effects').

'Aggrastat' prolonged bleeding time; however, the combined administration of 'Aggrastat' and ticlopidine did not additionally affect bleeding time.

Concomitant use of warfarin with 'Aggrastat' plus heparin was associated with an increased risk of bleeding.

'Aggrastat' is not recommended in thrombolytic therapy - concurrent or less than 48 hours before administration of tirofiban hydrochloride or concurrent use of drugs that increase the risk of bleeding to a relevant degree (e.g. oral anticoagulants, other parenteral GP IIb/IIIa inhibitors, dextran solutions). There is insufficient experience with the use of tirofiban hydrochloride in these conditions; however, an increased risk of bleeding is suspected.

4.6 Pregnancy And Lactation

Pregnancy

For tirofiban hydrochloride, no clinical data on exposed pregnancies are available. Animal studies provide limited information with respect to effects on pregnancy, embryonal/foetal development, parturition, and postnatal development. 'Aggrastat' should not be used during pregnancy unless clearly necessary.

Lactation

It is not known whether 'Aggrastat' is excreted in human milk but it is known to be excreted in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

No data are available on whether 'Aggrastat' impairs the ability to drive or operate machinery.

4.8 Undesirable Effects

Bleeding

The adverse event causally related to 'Aggrastat' therapy (used concurrently with unfractionated heparin and ASA) most commonly reported was bleeding, which was usually of a milder nature.

In the PRISM-PLUS study, the overall incidence of major bleeding using the TIMI criteria (defined as a haemoglobin drop of>50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade) in patients treated with 'Aggrastat' in combination with heparin was not significantly higher than in the control group. The incidence of major bleeding using the TIMI criteria was 1.4% for 'Aggrastat' in combination with heparin and 0.8% for the control group (which received heparin). The incidence of minor bleeding using the TIMI criteria (defined as a haemoglobin drop of>30 g/l with bleeding from a known site, spontaneous gross haematuria, haematemesis or haemoptysis) was 10.5% for 'Aggrastat' in combination with heparin and 8.0% for the control group. There were no reports of intracranial bleeding for 'Aggrastat' in combination with heparin or in the control group. The incidence of retroperitoneal bleeding reported for 'Aggrastat' in combination with heparin was 0.0% and 0.1% for the control group. The percentage of patients who received a transfusion (including packed red blood cells, fresh frozen plasma, whole blood cryoprecipitates and platelets) was 4.0% for 'Aggrastat' and 2.8% for the control group.

'Aggrastat' given with unfractionated heparin and ASA was associated with gastro-intestinal, haemorrhoidal and post-operative bleeding, epistaxis, gum bleeds and surface dermatorrhagia as well as oozing haemorrhage (haematoma) in the area of intravascular puncture sites (e.g. in cardiac catheter examinations) significantly more often than was unfractionated heparin and ASA alone.

Non-bleeding-associated adverse reactions

The most common adverse drug reactions (incidence over 1%) associated with 'Aggrastat' given concurrently with heparin, apart from bleeding, were nausea (1.7%), fever (1.5%) and headache (1.1%); nausea, fever and headache occurred with incidences of 1.4%, 1.1% and 1.2%, respectively, in the control group.

The incidence of adverse non-bleeding-related events was higher in women (compared to men) and older patients (compared to younger patients). However, the incidences of non-bleeding-related adverse events in these patients were comparable for the '“Aggrastat”' with heparin' group and the 'heparin alone' group.

[Common: (>1/100, <1/10)]

Nervous system and psychiatric disorders:

Common: headache

Gastrointestinal disorders:

Common: nausea

General disorders and administration site conditions:

Common: fever

Investigations

The most common changes of laboratory parameters associated with 'Aggrastat' related to bleeding: reduction of haemoglobin and haematocrit levels and an increased occurrence of occult blood in urine and faeces.

Occasionally during 'Aggrastat' therapy an acute fall in the platelet count or thrombocytopenia occurred. The percentage of patients in whom the platelet count fell to below 90,000/mm³ was 1.5%. The percentage of patients in whom the platelet count fell to less than 50,000/mm³ was 0.3%. These decreases were reversible upon discontinuation of 'Aggrastat'. Acute and severe platelet decreases have been observed in patients with no prior history of thrombocytopenia upon re-administration of GPIIb/IIIa receptor antagonists.

The following additional adverse reactions have been reported infrequently in post-marketing experience; they are derived from spontaneous reports for which precise incidences cannot be determined:

Blood and lymphatic system disorders:

Intracranial bleeding, retroperitoneal bleeding, haemopericardium, pulmonary (alveolar) haemorrhage, and epidural haematoma in the spinal region. Fatal bleedings have been reported rarely.

Acute and/or severe (<20,000/mm³) decreases in platelet counts which may be associated with chills, low-grade fever or bleeding complications (see Investigations above)

Immune system disorders:

Severe allergic reactions (e.g., bronchospasm, urticaria) including anaphylactic reactions. The reported cases have occurred during initial treatment (also on the first day) and during readministration of tirofiban. Some cases have been associated with severe thrombocytopenia (platelet counts <10,000/mm³).

4.9 Overdose

Inadvertent overdosage with tirofiban hydrochloride occurred in the clinical studies, up to 50 microgram/kg as a three minute bolus or 1.2 microgram/kg/min as an initial infusion. Overdosage with up to 1.47 microgram/kg/min as a maintenance infusion rate has also occurred.

a) Symptoms of overdosage

The symptom of overdosage most commonly reported was bleeding, usually mucosal bleeding and localised bleeding at the arterial puncture site for cardiac catheterisation but also single cases of intracranial haemorrhages and retroperitoneal bleedings (see also 4.4 'Special warnings and precautions for use' and 5.1 'Pharmacodynamic properties', PRISM-PLUS study).

b) Measures

Overdosage with tirofiban hydrochloride should be treated in accordance with the patient's condition and the attending physician's assessment. If treatment of haemorrhage is necessary, the 'Aggrastat' infusion should be discontinued. Transfusions of blood and/or thrombocytes should also be considered. 'Aggrastat' can be removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC-Code: B01A C17

Tirofiban hydrochloride is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban hydrochloride prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Tirofiban hydrochloride leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation.

The extent of this inhibition runs parallel to the tirofiban hydrochloride plasma concentration.

In the target population the recommended dosage of 'Aggrastat', in the presence of unfractionated heparin and ASA, produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.

PRISM-PLUS study

The double-blind, multicentre, controlled PRISM-PLUS study compared the efficacy of tirofiban and unfractionated heparin (n=773) versus unfractionated heparin (n=797) in patients with unstable angina or acute non-Q-wave myocardial infarction (NQWMI).

Patients had to have prolonged, repetitive anginal pain, or post-infarction angina within 12 hours prior to randomisation, accompanied by new transient or persistent ST-T wave changes (ST depression or elevation

In this study, patients were randomised to either

− 'Aggrastat' (30 minute loading infusion of 0.4 microgram/kg/min followed by a maintenance infusion of 0.10 microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately two times control),

− or heparin alone (bolus of 5,000 U followed by an infusion of 1,000 U/hr titrated to maintain an APTT of approximately two times control).

All patients received ASA unless contra-indicated; 300-325 mg orally per day were recommended for the first 48 hours and thereafter 80-325 mg orally per day (as determined by the physician). Study drug was initiated within 12 hours after the last anginal episode. Patients were treated for 48 hours, after which they underwent angiography and possibly angioplasty/atherectomy, if indicated, while tirofiban hydrochloride was continued. Tirofiban hydrochloride was infused for a mean period of 71.3 hours.

The combined primary study end-point was the occurrence of refractory ischaemia, myocardial infarction or death at seven days after the start of tirofiban hydrochloride.

The mean age of the population was 63 years; 32% of patients were female. At baseline approximately 58% of patients had ST segment depression; 53% had T-wave inversions; 46% of patients presented with elevated cardiac enzymes. During the study approximately 90% of patients underwent coronary angiography; 30% underwent early angioplasty and 23% underwent early coronary artery bypass surgery.

At the primary end-point, there was a 32% risk reduction (RR) (12.9% vs. 17.9%) in the tirofiban hydrochloride group for the combined end-point (p=0.004): this represents approximately 50 events avoided for 1,000 patients treated. Results of the primary end-point were principally attributed to the occurrence of myocardial infarction and refractory ischaemic conditions.

After 30 days the RR for the combined end-point (death/myocardial infarction/refractory ischaemic conditions/readmissions for unstable angina) was 22% (18.5% vs. 22.3%; p=0.029).

After six months the risk of the combined end-point (death/myocardial infarction/refractory ischaemic conditions/readmissions for unstable angina) was reduced by 19% (27.7% vs. 32.1%; p=0.024).

Regarding the most commonly used double combined end-point, death or myocardial infarction, the results at seven days, 30 days and six months were as follows: at seven days for the tirofiban group there was a 43% RR (4.9% vs. 8.3%; p=0.006); at 30 days the RR was 30% (8.7% vs. 11.9%; p=0.027) and at 6 months the RR was 23% (12.3% vs. 15.3%; p=0.063).

The reduction in the incidence of myocardial infarctions in patients receiving 'Aggrastat' appeared early during treatment (within the first 48 hours) and this reduction was maintained through six months, without significant effect on mortality.

In the 30% of patients who underwent angioplasty/atherectomy during initial hospitalisation, there was a 46% RR (8.8% vs. 15.2%) for the primary combined end-point at 30 days as well as a 43% RR (5.9% vs. 10.2%) for 'myocardial infarction or death'.

Based on a safety study, the concomitant administration of 'Aggrastat' with enoxaparin (n=315) was compared to the concomitant administration of 'Aggrastat' with unfractionated heparin (n=210) in patients presenting with unstable angina and non-Q-wave myocardial infarction. A 30 minute loading dose of tirofiban (0.4 microgram/kg/min) was followed by a maintenance infusion of 0.1 microgram/kg/min for up to 108 hours. Patients randomised to the enoxaparin group received a 1.0 mg/kg subcutaneous injection of enoxaparin every 12 hours for a period of at least 24 hours and a maximum duration of 96 hours. Patients randomised to the unfractionated heparin group received a 5000-unit intravenous bolus of unfractionated heparin followed by a maintenance infusion of 1000 units per hour for at least 24 hours and a maximum duration of 108 hours. The total TIMI bleed rate was 3.5% for the tirofiban/enoxaparin group and 4.8% for the tirofiban/unfractionated heparin group. Cutaneous bleeds and oral bleeds occurred more frequently in patients randomised to the enoxaparin group versus the unfractionated heparin group. Catheter site bleeds were more common in the enoxaparin group as compared to the unfractionated heparin group. Patients randomised to the enoxaparin group who subsequently required PCI were switched to unfractionated heparin peri-procedurally with the dose titrated to maintain an ACT of 250 seconds or higher. Although there was a significant difference in the rates of cutaneous bleeds between the two groups (29.2% in the enoxaparin converted to unfractionated heparin group and 15.2% in the unfractionated heparin group), there were no TIMI major bleeds (see also 4.4 'Special warnings and precautions for use') in either group. The efficacy of 'Aggrastat' in combination with enoxaparin has not been established.

Patients most likely to benefit from 'Aggrastat' treatment are those at high risk of developing myocardial infarction within the 3-4 days after onset of acute angina symptoms. According to epidemiological findings, a higher incidence of cardiovascular events has been associated with certain indicators, for instance: age, elevated heart rate or blood pressure, persistent or recurrent ischaemic cardiac pain, marked ECG changes (in particular ST-segment abnormalities), raised cardiac enzymes or markers (e.g. CK-MB, troponins) and heart failure.

5.2 Pharmacokinetic Properties

Distribution

Tirofiban is not strongly bound to plasma protein, and protein binding is concentration-independent in the range of 0.01–25 microgram/ml. The unbound fraction in human plasma is 35%.

The distribution volume of tirofiban in the steady state is about 30 litres.

Biotransformation

Experiments with ¹⁴C-labelled tirofiban showed the radioactivity in urine and faeces to be emitted chiefly by unchanged tirofiban. The radioactivity in circulating plasma originates mainly from unchanged tirofiban (up to 10 hours after administration). These data suggested limited metabolisation of tirofiban.

Elimination

After intravenous administration of ¹⁴C-labelled tirofiban to healthy subjects, 66% of the radioactivity was recovered in the urine, 23% in the faeces. The total recovery of radioactivity was 91%. Renal and biliary excretion contribute significantly to the elimination of tirofiban.

In healthy subjects the plasma clearance of tirofiban is about 250 ml/min. Renal clearance is 39–69% of plasma clearance. The half-life is about 1.5 hours.

Gender

The plasma clearance of tirofiban in patients with coronary heart disease is similar in men and women.

Elderly patients

The plasma clearance of tirofiban is about 25% less in elderly (>65 years) patients with coronary heart disease in comparison to younger (

Ethnic groups

No difference was found in the plasma clearance between patients of different ethnic groups.

Coronary Artery Disease

In patients with unstable angina pectoris or NQWMI the plasma clearance was about 200 ml/min, the renal clearance 39% of the plasma clearance. The half-life is about two hours.

Impaired renal function

In clinical studies, patients with decreased renal function showed a reduced plasma clearance of tirofiban depending on the degree of impairment of creatinine clearance. In patients with a creatinine clearance of less than 30 ml/min, including haemodialysis patients, the plasma clearance of tirofiban is reduced to a clinically relevant extent (over 50%) (see also 4.2 'Posology and method of administration'). Tirofiban is removed by haemodialysis.

Liver failure

There is no evidence of a clinically significant reduction of the plasma clearance of tirofiban in patients with mild to moderate liver failure. No data are available on patients with severe liver failure.

Effects of other drugs

The plasma clearance of tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug in a sub-set of patients (n=762) in the PRISM study. There were no substantial (>15%) effects of these drugs on the plasma clearance of tirofiban: acebutolol, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glibenclamide, unfractionated heparin, insulin, isosorbide, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, paracetamol, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam.

The pharmacokinetics and pharmacodynamics of 'Aggrastat' were investigated when concomitantly administered with enoxaparin (1mg/kg subcutaneously every 12 hours) and compared with the combination of 'Aggrastat' and unfractionated heparin. There was no difference in the clearance of 'Aggrastat' between the two groups.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Tirofiban crosses the placenta in rats and rabbits.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water for injections, hydrochloric acid and/or sodium hydroxide (for pH adjustment).

6.2 Incompatibilities

Incompatibility has been found with diazepam. Therefore, 'Aggrastat' and diazepam should not be administered in the same intravenous line.

6.3 Shelf Life

Three years.

From a microbiological point of view the diluted solution for infusion should be used immediately. If not used immediately, in use storage conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not freeze. Keep container in outer carton, to protect from light.

6.5 Nature And Contents Of Container

50 ml Type I glass vial.

6.6 Special Precautions For Disposal And Other Handling

No incompatibilities have been found with 'Aggrastat' and the following intravenous formulations: atropine sulfate, dobutamine, dopamine, epinephrine HCl, furosemide, heparin, lidocaine, midazolam HCl, morphine sulfate, nitroglycerin, potassium chloride, propanolol HCl and famotidine injection.

'Aggrastat' concentrate for solution for infusion must be diluted before use. See 4.2 'Posology and method of administration'.

7. Marketing Authorisation Holder

Iroko Cardio (UK) Ltd., 201 Bishopsgate, London, EC2M 3AF, UK.

8. Marketing Authorisation Number(S)

PL 35173/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

First authorisation: 15 July 1999

First renewal: 14 May 2003

10. Date Of Revision Of The Text

30 November 2009

11. LEGAL STATUS

POM

^* in the following 'Aggrastat' means 'Aggrastat' concentrate for solution for infusion.

^* in the following 'Aggrastat' means 'Aggrastat' concentrate for solution for infusion.

^**TIMI major bleeds are defined as a haemoglobin drop of> 50 g/l with or without an identified site, intracranial haemorrhage, or cardiac tamponade. TIMI minor bleeds are defined as a haemoglobin drop of> 30 g/l by