AUSTRALIA PATENTS ACT 1990 REGULATION 3,2 Name of Applicant: LUITPOLD PHARMACEUTICALS, INC Actual Inventor/s: Mary Jane Helenek; Marc L. Tokars; and Richard P. Lawrence. Address for Service: E. F. WELLINGTON & CO Patent and Trade Mark Attorneys, 312 St. Kilda Road, Melbourne, Southbank, Victoria, 3006. Invention Title: "METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON" Details of Associated Provisional Applications Nos: The following statement is a ful description of this invention including the best method of Performing it known to us.
CROSS-REFERENCE TO RELATED APPLICATIONS [0001J This application is a 'divisional application derived from Australian Patent Application No 2007205167 (PCTJUS2W07,000176: WO 2007/08 1744), claiming priority of US Application Nos. 60/757119 and 11/620986, the entire text of which arc hereby incorporated herein by reference. [0002] The present invention generally relates to treatment of iron-related conditions with iron carbohydrate complexes. BACKGROUND £00031 Parenteral iron therapy is known to be effective in a variety of diseases and To conditions including, but not limited to, severe Iron deficiency, iron deficiency anemia, problems of intestinal iron absorption, intestinal Iron intolerance, cases where regular Intake of an oraf iron preparation is not guaranteed, iron deficiency where there is no response to oral therapy (eg,, dialysis patients), and situations where iron stores are scarcely or not at all formed but would be Important for further therapy (eg., in combination with erythropoetin). Geisser et at, 15 Aranemittelforschung (1992)42(12). 1439~1452. There exist various commercIally available parenteral Iron formulations. But many currently available parenteral ion drugs, while purportedly effective at repleting iron stores, have health risks and dosage limitations associated with their use. (00 041 Currently available parenteral iron formulations approved for use in the US, 20 include iron dextran (e.g, InFed, Dexterrum), sodium ferric gluconate complex in sucrose (Ferrlecit), and iron sucrose (Venofer), Although serious and life-threatening reactions occur most frequently with iron dextran, they are also known to occur with other parenteral iron products. In addition, non-life threatening reactions such as arthralgia, back pain, hypotension. fever, myalgia,. pruritus, vertigo, and vomiting also occur. These reactions, while not life 25 threatening, often preclude further dosing and therefore iron repletion (00051 ron dextran, the first parenteral iron product available in the United States (US), has been associated with an incidence of anaphylactoid-type reactions (tel dyspnea, wheezing. chest pain, hypotension, urticaria, angioedema). See generally Fishbane, Am J Kidney Dis (2003) 41 (SSuppl), 18-26: Landry et at (2005) Am J Nephrol 25, 400-410, 407. This 30 high incidence of anaphylactoid reactions is believed to be caused by the formation of antibodies to the dextran moiety. Other parenteral iron products (e.g, iron sucrose and iron gluconate) do not contain the dextran moiety, and the incidence of anaphylaxis with these products is markedly ower. Fishbane, Am J Kidney Dis (2003) 41(SSuppl), 18-26; Geisser et at, Arzneimittelforschung (1992) 42(12), 1439-52, However, the physical characteristics of, for
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example, iron gluconate and iron sucrose lead to dosage and administration rate limitations, Negative characteristics include high pH, high osmolarity, low dosage limits (e.g., maximum 500 mg iron once per week, not exceeding 7 mg iron/kg body weight), and the long duration of administration (e.g., 100 mg iron over at least 5 minutes as an injection; 500 mg iron over at least 5 3.5 hours as a drip infusion), Furthermore, injectable high molecular mass substances produce more allergic reactions than the corresponding low molecular mass substances. Geisser et at. (1092) Arznsimlftelforschung 42: 1439-1452. too61 Ferumoxytol is a newer parenteral iron formulation but limited Information Is available as to its efficacy and admInistration. Sea e.g., Landry et alt (2005) Am J Nephrol 25, 10 400-410, 408; and Spinowitz etal. (2005) Kidney intl 68, 1801-1807; U.S. Patent No. 6,599,498. k o007 1 Various pharmacokinetic studies suggest that doses of iron complexes higher than 200 mg of iron are generally unsuitable and that the conventional therapy model prescribes repeated applications of lower doses over several days. See Geisser et a., (1992) Arzneirittelforschung 42: 1439-1452. For example, to achieve iron repletion under current 15 therapy models, a total dose of I g typically requires S to 10 sessions over an extended period of time. These delivery modes incur significant expense for supplies such as tubing and infusate, costly nursing time, multiple administrations, and patient inconvenience, SUMMARY OF THE INVENTION [00081 Among the various aspects of the present invention is the provision of a 20 method of treatment of iron-associated diseases, disorders, or conditions with iron formulations. Briefly, therefore, the present invention Is directed to use of iron carbohydrate complexes that can be administered parenteral y at relatively high single unit dosages, thereby providing a safe and efficient means for delivery of a total dose of iron in fewer sessions over the course of therapeutic treatment. 2$ [o og] The p-resent teachings include methods of treatIng a disease, disorder, or condition characterized by Iron deficiency or dysfunctional iron metabolism through the administration of at least 0.6 grams of elemental iron via a single unit dosage of an iron carbohydrate complex to a subject that is in need of such therapy. ( 0101 in various embodiments, the method treats anemia. In some embodiments, 30 the anemia is an iron deficiency anemia, such as that associated with chronic blood loss; acute blood loss; pregnancy; childbirth; childhood development; psychomotor and cognitive development in children; breath holding spells; heavy uterine bleeding; menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic internal bleeding; gastrointestinal bleeding; parasitic infections; chronic kidney disease: dialysis; surgery or acute trauma: and 3$ chronic ingestion of alcohol, chronic ingestion of salicylates, chronic ingestion of steroids; chronic ingestion of non-steroidial anti-inflammatory agents, or chronic ingestion of erythropoiesis stimulating agents, In some aspects, the anemia is anemia of chronic disease, such as rheumatoid arthritis; cancer; Hodgkins leukemia; non-Hodgkins leukemia; cancer chemotherapy; inflammatory bowel disease: ulcerative colitis thyroiditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Sojgren's syndrome; 5 congestive heart failure / cardiomyopathy; or idiopathic geriatric anemia, in some embodiments, the anemia is due to impaired iron absorption or poor nutrition, such as anemia associated with' Crohn's Disease; gastric surgery; ingestion of drug products that inhibit iron absorption; and chronic use of caiciurh in various embodiments, the method treats restless leg syndrome; blood donation; Parkinson's disease; hair loss; or attention deficit disorder, 10 ' [10011j In various embodiments, the single dosage unit of elemental iron is between at least about 0,6 grams and 2.5 grams, In some embodiments, the single dosage unit of elemental iron is at least about 0.7 grams; at least about 0. grams; at least about 0.9 grams; at least about 1.0 grams; at least about 1.1 grams; at least about 1.2 grams;,at least about 1.3 grams; at least about 1,4 grams; at least about 1.5 grams; at least about 1.6 grams; at least about 1.7 grams; at 15 least about 1.8 grams; at least about 1.9 grams; at least about 2,0 grams; at least about 2.1 grams; at least about 2.2 grams; at least about 2.3 grams; at least about 2A grams; or at least about 2,5 grams. [00121 in various embodiments, the single dosage unit of elemental iron is administered in about 15 minutes or less, !n some embodiments, the single dosage unit of 20 elemental iron is administered in about 10 minutes or less, about 5 minutes or less, or about 2 minutes or less. [00133 In various embodiments, the subject does not experience a significant adverse reaction to the single dosage unit administration, [00141 In various embodiments, the iron carbohydrate complex has a pH between 25 about 5.0 to about 7.0; physiological osmolarity; an iror core size no greater than about 9 nm; a mean diameter particle size no greater than about 35 nm; a blood half-life of between about 10 hours to about 20 hours; a substantially non-immunogenic carbohydrate component; and substantially no cross reactivity with anti-dextran antibodies. to oi) an various embodiments, the iron carbohydrate complex contains about 24% to 30 about 32% elemental iron; contains about 25% to about 50% carbohydrate; has a molecular weight of about 90,000 daltons to about 800,000 daltons, or some combination thereof, In various embodiments, the iron carbohydrate complex is an iron monosaccharide complex, an iron disaccharide complex, or an iron polysaccharide complex In some embodiments, the iron carbohydrate complex is iron carboxymaltose complex, iron mannitol 35 complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, or an iron hydrogenated dextran complex, In some embodiments, the iron carbohydrate complex is an iron polyglucose sorbitol carboxymethyl ether complex. in some preferred embodiments, the iron carboxymaltose complex contains about 24% to about 32% elemental iron, about 25% to about 50% carbohydrate, and is about 100,000 daltons to about 350,000 daltons, In some preferred embodiments, the iron carboxymaltose complex is obtained 5 from an aqueous solution of iron (iI) salt and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution at a pH value within the alkaline range, wherein, when one maltodextrin is applied, its dextrose equivalent lies between 5 and 20, and when: a mixture of several maltodextrins is applied, the dextrose equivalent lies between 5 and 20 and the dextrose equivalent of each Individual maltodextrin contained in the mixture lies 10 between 2 and 20. In some preferred embodiments, the iron carboxymaltose complex has a chemical formula of [FeO, (OHXy (H2,O)i R{(CeH1oOs)m (Cb), 1, where n is about 103, m is about 8, 1 is about 11, and k Is about 4; contains about 28% elemental iron; and has a molecular weight of about 150,000 Da, In some preferred embodiments, the iron carboxymaitose complex is polynuclear iron (111)hydroxide 4(R)-(poy-(1 -- 4)-0-a-glucopyranosyl)-oxy-2(R).3(S),5(R),6 1$ tetrahydroxy-hexanoate. fo 016] In various embodiments, the iron carbohydrate complex comprises an iron core with a mean iron core size of no greater than about 9 nm. In some embodiments, the mean iron core size is at least about I nm but no greater than about 9 nm; at least about 3 nm but no greater than about 7 nm; or at least about 4 nm but not greater than about 5 nm. 20 [00171 In various embodimerts, the mean size of a particle of the iron carbohydrate complex is no greater than about 35 rim, In some embodiments, the particle mean size is no greater than about 30 nm In some embodiments, the particle mean size is no greater than about 25 nm. In some ambodiments, the particle mean size is no greater than about 20 nm; no greater than about 15 nm; no greater than about 10 am, or at least about 6 nm but no greater 25 than about 7 nm. [001$e) In various embodiments, the iron carbohydrate complex is administered parenterally, for example intravenously or Intramuscularly, in some embodiments, the iron carbohydrate complex is intravenously infused, In certain embodiments, the single unit dose of Iron carbohydrate complex is intravenously infused at a concentration of about 1000 mg 30 elemental iron in about 200 mi to about 300 mi of diluent, for example, about 250 ml of diluent or about 215 ml of diluent, In some embodiments, the iron carbohydrate complex Is intravenously injected as a bolus, In certain embodiments, the Iron carbohydrate complex is intravenously injected as a bolus at a concentration of about 1000 ng elemental iron in about 200 ml to about 300 ml of diluent, for example, about 250 mi of diluent or about 215 mI of diluent. n some 35 embodiments, the iron carbohydrate complex Is intramuscularly infused at a concentration of about 1000 mg elemental Iron in about 200 mi to about 300 ml of diluent, for example, about 250 ml of diluent or about 215 ml of diluent, In some embodiments, the iron carbohydrate complex is -4intramuscularly infused at a concentration of about 500 mg elemental iron in less than about 10 ml diluent. f03c9) In various embodiments, the method also includes second administration: o the iron carbohydrate complex upon recurrence of at least one symptom of the treated disease, 5 disorder, or condition. [002 oi In various embodiments, the method also Includes a second administration of the iron carbohydrate complex after I day to 12 months after the first administration. (0 0211 In a preferred embodiment, the method of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism comprises 10 intravenously administering to a subject in need thereof an Iron carboxymaltose complex in a single dosage unit of at least about 1000 mg of elemental iron in about 200 mi to about 300 ni of diluent in about 5 minutes or less; wherein the iron carboxymaltose complex comprises an iron core with a mean iron core size of at least about I nm but no greater than about 9 nm;'mean size of a particle of the iron carboxymaltose complex is no greater than about 35 nrm; and the iron 15 carboxymaltose complex is administered intravenously infused or intravenously injected at a concentration of about 1000 mig elemental iron in about 200 mI to about 300 ni of diluent, In some these embodiments, the iron carboxymaltose complex is polynuclear iron (11)-hydroxide 4(R)-(poly-(1 ) - pa In some these embodiments, the iron carboxymaitose complex is obtained from an aqueous solution of 20 iron (Ill) salt and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution at a pH value within the alkaline range, wherein, when one maltodextrin is applied, its dextrose equivalent Ies between about 5 and about 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent lies between about 5 and about 20 and the dextrose equivalent of each individual maltodextrin contained in the mixture lies 25 between about 2 and about 20, (00221 Other objects and features will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS t00231 Those of skill in the art will understand that the drawings, described below, are 30 for illustrative purposes only, The drawings are not intended to limit the scope of the present teachings In any way. (0024) FIG 1 is a series of electron micrographs that depict the particle size of three iron carbohydrate complexes. FIG 1A is an electron micrograph depicting the particle size of Dexferrum (an irori dextran), FIG IS is an electron micrograph depicting the particle size of 35 Venofer (an iron sucrose), FIG IC is an electron micrograph depicting the particle size of polynuclear iron (1ll-hydroxide 4(R)poy-(1-4)-O-a-giucopyranosyl)oxy-2(R),3(S),S(R),6 tetrahydroxy-hexanoate (WiT-45", an iron carboxymattose complex) [0025] FIG 2 is a schematic representation of an exemplary iron carboxymaltose complex. 5 DETAILED DESCRIPTION OF THEINVENTION (002 cj The present invention makes use of Iron carbohydrate complexes that can be administered parenterafiy at relatively high single unit dosages for the therapeutic treatment of a variety of iron-associated diseases, disorders, or conditions. Generallty states indicative of a need for therapy with high single unit dosages of iron carbohydrate complexes include, but are 10 not limited to iron deficiency anemia, anemia of chronic disease, and states characterized by dysfunctional iron metabolism. Efficacious treatment of these, and other, diseases and conditions with parenteral iron formulations (supplied at lower single unit dosages than those described herein) is generally known in the art. See e~g., Van Wyck et alt (2004)4) Am Soc Nephrol 15, 591-S92. The present invention Is directed to use of iron carbohydrate complexes that can be 15 administered parenterally at relatively high single unit dosages, thereby providing a safe and efficient means for delivery of a total dose of iron in fewer sessions over the course of therapeutic treatment. (0027 Iron deficiency anemia is associated with, for example, chronic blood loss; acute blood loss; pregnancy; childbirth; childhood development; psychomotor and cognitive 20 development in children; breath holding spells; heavy uterine bleeding; menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic internal bleeding; gastrointestinal bleeding; parasitic infections; chronic kidney disease; dialysis; surgery or acute trauma; and chronic ingestion of alcohol, chronic ingestion of salicylates, chronic ingestion of steroids; chronic ingestion of nonsteroldial anti-inflammatory agents, or chronic ingestion of erythropoiesis 2$s stimulating agents, (0 028) Anemia of chronic disease is associated with, for example, rheumatoid arthritis; cancer; Hodgkins leukemia; non-Hodgkins leukemia; cancer chemotherapy; inflammatory bowel disease; ulcerative colitis thyroliditis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; scleroderma; mixed connective tissue disease: Sojgren's syndrome 30 congestive heart failure i cardiomyopathy; and idlopathic geriatric anemia. (0 0 2 9 Anemia is also associated with, for example, Crohn's Disease; gastric surgery Ingestion of drug products that inhibit iron absorption; and chronic use of calcium. (0030]1 States characterized by dysfunctional iron metabolIsm and treatable with the single unit dosages of iron carbohydrate complexes described herein include, but are not limited 35 to, restless leg syndrome; blood donation; Parkinson's disease; hair loss; and attention deficit disorder; [0031] Again, each of the above listed states, diseases, disorders, and conditions, as well as others, can benefit from the treatment methodologis described herein. Generally, treating a state, disease, disorder, or condition includes preventing or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, 5 disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof, Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can Include relieving the disease, e.g, causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical 10 symptoms, [00321 The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. Measures of efficacy of iron replacement therapy are generally based on measurement of iron-related parameters in blood. The aim of treatment is usually to return both Hb and iron stores to normal levels, Thus, efficacy of iron replacement 15 therapy can be interpreted in terms of the ability to normalise Hoib levels and iron stores. The effectiveness of treatment with one or more single unit doses of iron carbohydrate complex, as described herein, can be demonstrated, for example, by improvements in ferritin and transferrin saturation, and in raising hemoglobin levels in anemic patients, Iron stores can be assessed by interpreting serum ferritin levels, TfS is frequently used, in addition, to diagnose absolute or 20 functional Iron deficiencies, In patients with iron deficiency, serum transferrin is elevated and will decrease following successful iron treatment. (0033) Administration [ 034) Methods of treatment of various diseases, disorders, or conditions with iron complex compositions comprise the administration of the complex in single unit dosages of at 2$ least 0.6 grams of elemental iron to about at least 2,5 grams of elemental iron, Administration of single unit dosages can be, for example, over pre-determined time intervals or in response to the appearance and/or reappearance of symptoms, For example, the iron carbohydrate complex can be re-administered upon recurrence of at least one symptom of the disease or disorder, As another example, the iron carbohydrate complex can be re-administered at some time period 30 after the initial administration (e.g,, after 4 days to 12 months). [0035 Any route of delivery of the single unit dose of iron carbohydrate complex is acceptable so long as iron from the iron complex is released such that symptoms are treated. The single unit dose of iron carbohydrate complex can be administered parenterally. for example intravenously or intramuscularly, Intravenous administration can be delivered as a bolus or 35 preferably as an infusion. For example, the single unit dose of iron carbohydrate complex can be intravenously infused at a concentration of about 1000 mg elemental iron in about 200 ml to about 300 ml of diluent, preferably about 215 mi of diluent or about 250 mi of diluent, The iron -7carbohydate complex can be intravenously injected as a bolus. For example, the Iron carbohydrate complex can be intravenously injected as a bolus at a concentration of about 1000 g elemental iron in about 200 mi to about 300 mi of diluent, preferably about 215 ml of diluent or about 250 ml of dluent The iron carbohydrate complex can be intramuscularly infused at a 5 concentration of, for example, about 1000 mg elemental Iron In about 200 mi to about 300 mi of diluent, preferably, about 250 mi of diluent or about 215 ml of diluent. If applied as an infusion, the iron carbohydrate complex can be diluted with sterile saline (e.g, polynuclear iron (Ill hydroxide 4(RHpoly-4-*4)0O-e glcopyranosy)Oxy 2( R),3(SXS(R ),-tetrahydroxy-iexanoate (NvIT45") 0,9% mN NaCI or 500 mg iron In up to 250 mL NaC ) The iron carbohydrate complex 10 can be intravenously injected as a bolus without dilution. As an example, the iron carbohydrate complex can be intramuscularly Injected at a concentration of about 500 mg elemental iron in less than about 10 ml diluent, preferably about 5 ml. 0036 6 General y, total iron dosage will depend on the iron deficit of the patient. One skilled in the art can tailor the total iron dose required for a subject while avoiding iron overload, 15 as overdosing with respect to the total required amount of iron has to be avoided, as is the case for all iron preparations. ( 00371 The total Iron dosage can be delivered as a single unit dosage or a series of single unit dosages. An appropriate single unit dosage level will generally be at least 0.6 grams of elemental iron, particularly at feast 0.7 grams; at least 0.8 grams; at least 0.9 grams; at least 20 1.0 grams: at least 1 1 grams; at least 12 grams; at least 1.3 grams; at least 1.4 grams; at least 1.5 grams; at least 1.5 grams; at least 1 .7 grams; at least 1.8grams; at least 1.0 grams; at least 2.0 grams; at least 21 grams: at least 2,2 grams; at least 2.3 grams; at least2.4 grams; or at least 2.5 grams. For example, a single unit dosage is at least 1.0 grams of elemental iron. As another example, a single unit dosage is at least 1 .5 grams of elemental iron. As a further 25 example, a single unit dosage is at least 2.0 grams of elemental iron. In yet another example a single unit dosage is at least 2.5 grams of elemental iron. (003a8 An appropriate single unit dosage level can also be determined on the basis of patient weight. For example, an appropriate single unit dosage level will generally be at least 9 mg of elemental iron per kg body weight, particularly at least 10.5 mg/kg, at least 12 mg/kg, at 30 least 13.5 mg/kg, at least 15 mg/kg, at least 16,5 mg/kg, at least 18 mg/kg, at least 19.5 mg/kg, at least 21 mg/kg, at least 22.5 mg/kg, at least 24 mg/kg. at least 25,5 mg/kg, at least 27 mg/kg, at least 28,5 mg/kg, at least 30 mg/kg, at least 31.5 mg/kg, at least 33 mg/kg, at least 34.5 mg/kg, at least 36 mg/kg, or at least 37.5 mg/kg. [003 91 Preferably, a single unit dosage can be administered in 15 minutes or less, 35 For example, the single unit dosage can be administered in 14 minutes or less, 13 minutes or less, 12 minutes or less, 11 minutes or less, 10 minutes or less, 9 minutes or less, 8 minutes or less. 7 minutes or less, 6 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, or 2 minutes or less. [00401 Administration of iron can occur as a one-time delivery of a single unit dose or over a course of treatment involving delivery of multiple single unit doses, Multiple single unit 5 doses can be administered, for example, over pre-determined time intervals or in response to the appearance and reappearance of symptoms, The frequency of dosing depends on the disease or disorder being treated, the response of each individual patient, and the administered amount of elemental iron. An appropriate regime of dosing adequate to allow the body to absorb the iron from the bloodstream can be, for example, a course of therapy once every day to once every 10 eighteen months, [00411 Such consecutive single unit dosing can be designed to deliver a relatively high total dosage of iron over a relatively low period of time. For example, a single unit dose (ag~, 1000 mg) can be administered every 24 hours. As illustration, a total dose of 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg of elemental iron can be delivered via consecutive daily 15 single unit doses of about 600 mg to about 1000 mg of elemental iron. Given that a single unit dose of 1000 mg can be intravenously introduced into a patient in a concentrated form over, for example, two minutes, such administrative protocol provides a practitioner and patient with an effective, efficient, and safe means to deliver elemental iron, [0 042] As another example, a single unit dose can be administered every 3-4 days, 20 As a further example, a single unit dose can be administered once per week. Alternatively, the single unit doses of iron complex may be administered ad hoc, that is, as symptoms reappear, as long as safety precautions are regarded as practiced by medical professionals, [0043) it will be understood, however, that the specific dose and frequency of administration for any particular patient may be varied and depends upon a vadety of factors, 25 including the activity of the employed iron complex, the metabolic stability and length of action of that complex, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity and nature of the particular condition, and the host undergoing therapy. [00441 The following provides but a few examples of treatment protocols for various 30 diseases or disorders. [0451 Iron carbohydrate complex can be given as a single unit dose for the treatment of Restless Leg Syndrome. For example, 1000 mg of elemental iron from an iron carboxymaltose (e.g, polynuclear iron (I1I)-hydroxide 4(R )-(poly-( 1 -4)-O-aglucopyranosyi)-oxy 2(R),3(S),5(R),6-tetrahydroxy-hexanoate) can be intravenously injected as a single dose (e.g, 35 1.5-5 mg iron/mi in normal saline) to a subject suffering from Restless Leg Syndrome. A single intravenous treatment can provide relief of symptoms for an extended period of time, -9approximately two to twelve months, although relief may be granted for shorter or longer periods, See US, Patent Pub. No. 2004/0180849, incorporated herein by reference. If desired, post infusion changes in central nervous system iron status can be monitored using measurements of cerebral spinal fluid (CSF) fertitin (and other iron-related proteins) and of brain iron stores using 5 MRI, Post-infusion changes in Restless Leg Syndrome are assessed using standard subjective (e.g,, patient diary, rating scale) and objective (e.g., P50, SIT, Leg Activity Meters) measues of clinical status. If desired, to better evaluate RLS symptom amelioration, CSF and serum iron values, MRI measures of brain iron and full clircal evaluations with sleep and immobilization tests are obtained prior to treatment, approximately two weeks after treatment, and again twelve 10 months later or when symptoms retum, Clinical ratings, Leg Activity Meter recordings and serum ferritin are obtained monthly after treatment. CSF ferritin changes can also be used to assess symptom dissipation. to 0461 Iron carbohydrate complex can be given as a single unit dose for the treatment of iron deficiency anemia secondary to heavy uterine bleeding. For example, a single unit dose i5 of 1,000 mg of elemental iron from an iron carboxymaltose in about 250 cc normal saline can be intravenously injected into a subject suffering from iron deficiency anemia secondary to heavy uterine bleeding over 15 minutes every week until a calculated iron deficit dose has been administered. The iron deficit dose can be calculated as follows: If baseline TSAT <20% or Baseline Feruitin < 50 ng/ml: 20 Dose = Baseline weight (kg) x (15-Baseline Hgb [g/dL]) x 2.4 + 500 mg OR if baseline TSAT >20% and Baseline Ferritin > 50 ngf/nL: Dose = Baseline weight (kg) x (15-Baseline Hgb [g/dL]) x 2.4 25 (NOTE: Baseline Hgb equals the average of the last two central lab Hgb's) (004'71 Iron carbohydrate complex can be given as a single unit dose for the treatment of iron deficiency anemia. A subject diagnosed as suffering from iron deficiency anemia can be, for example, intravenously injected with a dose of 1,000 mg of iron as VIT- 45 (or 15 mg/kg for 30 weight < 6 kg) In 250 cc of normal saline over 15 minutes. Subjects with iron deficiency anemia secondary to dialysis or non-dialysis dependent-Chronic Kidney Disease (CKD) as per K/DOQI guidelines will generally have Hgb < 12 g/dt; ThSAT < 25%; and Ferritin <300 ng/mL Subjects with iron deficiency anemia secondary to inflammatory Bowel Disease will generally have Hgb < 12 g/dL; TSAT < 25%; and Ferritin < 300 ng/mL, Subjects with iron deficiency anemia secondary 35 to other conditions wil generally have Hgb < 12 g/dL; TSAT < 25%; and Ferritin < 100 ng/mL. (004 81 Subject in need thereof [00491 Single unit dosages of Intravenous iron described herein can be administered to a subject where there is a clinical need to deliver iron rapidly or in higher doses and/or in -10 subjects with functional iron deficiency such as those on erythropoietin therapy. A determination of the need for treatment with parenteral iron is within the abities of one skilled in the art. For example, need can be assessed by monitoring a patient's iron status, The diagnosis of Iron deficiency can be based on appropriate laboratory tests, for example, haernoglobin (Hb), serum $ ferritin, serum Iron, transferrin saturation (TfS), and hypochromic red cells., 005 03} A determination of the need for treatment with high dosages of parenteral iron can be also be determined through diagnosis of a patient as suffering from a disease, disorder, or condition that is associated with iron deficiency or dysfunctional iron metabolism, For example, many chronic renal failure patients receiving erythropoietin will require intravenous iron 10 to maintain target Iron levels. As another example, most hemodialysis patients will require repeated intravenous kon administration, due to dialysis-associated blood loss and resulting negative iron balance. [ Ist Monitoring frequency can depend upon the disease, disorder, or condition the patient is afflicted with or at risk for, For example, in a patient initiating erythropoietin therapy, 15 Iron Indices are monitored monthly. As another example, in patients who have achieved target range Hb or are receiving intravenous iron therapy, TSAT and ferritin levels can be monitored every 3 months. [10523 A patient's iron status can be indicative of an absolute or a functional iron deficiency, both of which can be treated with the compositions and methods described herein, 20 An absolute iron deficiency occurs when an insufficient amount of iron is available to meet the body's requirements. The insufficiency may be due to inadequate iron intake, reduced bioavailability of dietary iron, increased utilization of fron, or chronic blood loss. Prolonged iron deficiency can lead to iron deficiency anemia-a microcytic. hypochromic anemia In which there are inadequate iron stores. Absolute iron deficiency is generally indicated where TSAT <20% 25 and Ferritin <100 ng/mL. [00531 Functional iron deficiency can occur where there Is a failure to release iron rapidly enough to keep pace with the demands of the bone marrow for erythropoiesis, despite adequate total body iron stores. In these cases, ferritin levels may be normal or high, but the supply of iron to the erythron is limited, as shown by a low transferrin saturation and an increased 30 number of microcytIc, hypochromic erythrocytes. Functional iron deficiency can be characterized by the following characteristics: Inadequate hemoglobin response to erythropoletin; Serum ferritin may be normal or high; Transferrin saturation (TSAT) usually <20%; and/or reduced mean corpuscular volume (MCV) or mean corpuscular hemoglobin concentration (MCHC) in severe cases. Functional iron deficiency (.e, iron stores are thought to be adequate but unavailable for 35 iron delivery) is generally indicated where TSAT <20% and Fertin >100 ng/mL (00 543 Assessing the need for Intravenous iron therapy as described herein can be according to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. See NKF-K/DOQI, Clinical Practice Guidelines for Anemia of Chronic Kidney Disease (2000); Am J Kidney Dis (2001) 37(supp 1), S182-S236. The 0001 provides optimal clinical practices for the treatment of anemia in chronic renal failure, The DOQ1 guidelines specify intravenous iron treatment of kidney disease based on hemoglobin, transferrin saturation (TSAT), and ferritin 5 levels. [ 5095) Assessment of need for intravenous iron therapy can also be according to a patient's target iron level. For example, the target hemoglobin level of a patient can be selected as 11O g/dL to 12.0 g/dL (hematocrit approximately 33% to 36%), To achieve target hemoglobin with optimum erythropoietin doses, sufficient iron, supplied via an iron carbohydrate complex, is 10 provided to maintain TSAT 20% and ferritin >100 ng/mL. In erythropoletr-treated patients, if TSAT levels are below 20%, the likelihood that hemoglobin will rise or erythropoietin doses fall after iron administration is high, Achievement of target hemoglobin levels with optimum erythropoietin doses is associated with providing sufficient iron to maintain TSAT above 20%. L o[00563 Iron therapy can be given to maintain target hemoglobin while preventing iron 15 deficiency and also preventing iron overload, Adjusting dosage of iron to maintain target levels of hemoglobin, hematocrit, and laboratory parameters of iron storage is within the normal skill in the art, For example, where a patient is anemio or iron deficient, intravenous iron can be administered when a patient has a ferritin <800, a TSAT<60, and/or a Hemoglobin <12. Iron overload can be avoided by withholding iron for TSAT >50% and/or ferritin >800 ng/mL. 20 [00571 Where a patient is not anemic or iron deficient but is in need of iron administration, for example a patient suffering from Restless Leg Syndrome, hemoglobIn and ThSAT levels are not necessarily relevant, while ferritin >800 can still provides a general cut off point for administration. [OO551 Iron Carbohydrate Complex 25 0 o s 91 Iron carbohydrate complexes are commercially available, or have well known syntheses, Examples of iron carbohydrate complexes include iron monosaccharide complexes, iron disaccharide complexes, iron oligosaccharide complexes, and iron polysacchardde complexes, such as: iron carboxymaltose, iron sucrose, iron polyisomaltose (Iron dextran), iron polymaltose (iron dextrin), iron gluconate, iron sorbitol, iron hydrogenated dextran, which may be 30 further complexed with other compounds, such as sorbitol, citric acid and gluconic acid (for example iron dextrin-sorbito-citric acid complex and iron sucrose-gluconic acid complex), and mixtures thereof [00601 Applicants have discovered that certain characteristics of iron carbohydrate complexes make them amenable to administration at dosages far higher than contemplated by IS current administration protocols. Preferably, iron carbohydrate complexes for use in the methods described herein are those which have one or more of the following characteristics: a nearly neutral p-1 (e.g,, about 5 to about 7); physiological osmolarity; stable carbohydrate component; an iron core size no greater than about 9 nm; mean diameter particle size no greater than about 35 nm, preferably about 25 nm to about 30 nm; slow and competitive delivery of the complexed iron to endogenous iron blading sites; searm half4ife of over about 7 hours; low toxicity; non 5 immunogenic carbohydrate component; no cross reactivity with anti-dextran antibodies; and/or low risk of anaphylactoid I hypersensitivity reactions. (00611 It is within the skill of the art to test various characteristics of iron carbohydrate complexes as so determine amenability to use in the methods described herein For example, pH and osmolarity are straIghtforward determinations performed on a sample formulation. 10 Likewise, techniques such as electron micrograph imaging, transmission electron microscopy, and atomic force microscopy provide direct methods to analyze both iron core and particle size, See e~g., Figure 1; Table 1. The stabi fLy of the carbohydrate complex can be assessed through physicochemical properties such as kinetic characteristics, thermodynamic characteristics, and degradation kinetics, See Geisser et at, Arzneimittelforschung (1992) 42(12), 1439'1452, 15 Useful techniques to assess physical and electronic properties include absorption spectroscopy, X-ray diffraction analysis, transmission electron microscopy, atomic force microscopy, and elemental analysis, See Kudasheva et al (2004) J lnorg Biochem 98, 1757-1769. Pharmacodkinetlcs can be assessed, for example, by iron tracer experiments. Hypersensitivity reactions can be monitored and assessed as described in, for example, Bailie et al, (2005) 20 Nephrol Dial Transplant, 20(7), 1443-1449, Safety, efficacy, and toxicity in human subjects can be assessed, for example, as described in Spinowitz et at, (2005) Kidney intl 68, 1801-1807, (00621 A particularly preferred iron carbohydrate complex will have a pH between 5.0 7.0; physiological osmolarity; an Iron core size no greater than 9 nm; mean diameter particle size no greater than 30 nm; serum half-ife of over 10 hours; a non-immunogenic carbohydrate 25 component; and no cross reactivity with anti-dextran antibodies. One example of a preferred iron carbohydrate complex for use in the methods described herein is an iron carboxy-maltose complex (e.g., polynuclear iron (111)-hydroxide 4(R )-(poly-( -4)-O--glucopyranosyl)-oxy 2(R),3(S)(R),6-tetrahydroxy-hexanoate, "VIT-45"). Another example of a preferred iron carbohydrate complex for use in the methods described herein is a carboxyalikylated reduced 30 polysaccharide iron oxide complex (e.g., ferumoxytol, described in U.S. Patent No. 6,599,498). CC t 6 31 Preferably, an iron carbohydrate complex, for use in methods disclosed herein, contains about 24% to about 32% elemental iron, more preferably about 28% elemental iron. Preferably, an iron carbohydrate complex, for use in methods disclosed herein, contains about 25% to about 50% carbohydrate (e.g_ total glucose), Preferably, an iron carbohydrate 3$ complex, for use in methods disclosed herein, is about 90,000 daitons to about 800,000 daltons, more preferably 100,000 daltons to about 350,000 daltons. £0064) Iron carboxymaltose complex - 3 [0,0 65) One preferred Iron carbohydrate complex for use In the methods described herein is an iron carboxyrnaltose complex, An example of an iron carboxymaltose complex is polynuclear iron (I11)-hydroxide 4(R)-(poly-(1 -4)-OCa-glucopyranosy )-oxy-2(R),3(S),5(R),6 tetrahydroxy-hexanoate (VIT-45"). VIT-45 is a Type I polynuclear iron (111) hydroxide 5 carbohydrate complex that can be administered as parenteral iron replacement therapy for the treatment of various anemiae-related conditions as well as other iron-metabolismn related conditions. VIT-45 can be represented by the chemical formula: [FeOx(OH)y(H20)zn [(C6H1005)m (C6H12O7)}lk, where n is about 103, m Is about 8, t is about 1, and k is about 4). The molecular weight of VIT-45 is about 150,000 Da, An exemplary depiction of VITA is 10 provided in Figure 2. [00661 The degradation rate and physicochemical characteristics of the iron carbohydrate complex (e.g., VIT-45) make it an efficient means of parenteral iron delivery to the body stores. It is more efficient and less toxic than the lower molecular weight compile xes such as iron sorbitol/citrate complex, and does not have the same limitations of high pH and 15 osmalarity that leads to dosage and administration rate limitations in the case of, for example, iron sucrose and iron gluconate. [00671 The Iron carboxymaltose complex (eag, VIT-45) generally does not contain dextran and does not react with dextran antibodies; therefore, the risk of anaphylactoid /hypersensitivity reactions Is very low compared to Iron dextrant The iron carboxymaltose 20 complex (e.g, VIT-45) has a nearly neutral pH(5.0 to 7.0) and physiological osmolarity, which makes It possible to administer higher single unit doses over shorter time periods than other iron carbohydrate complexes. The iron carboxymaltose complex (e.g. VIT-45) can mimic physiologically occurring ferritin. The carbohydrate moiety of iron carboxymaltose complex (e.g., VIT45) is metabolized by the glycolytic pathway, Like iron dextran, the iron carboxymaitose 25 complex (e.g, VIT-45) is more stable than iron gluconate and sucrose, The iron carboxymattose complex (0.gVITE-45) produces a slow and competitive delivery of the complexed iron to endogenous iron binding sites resulting in an acute toxicity one-fifth that of iron sucrose. These characteristics of the iron carboxymaltose complex (e~g, VIT-45) allow administration of higher single unit doses over shorter periods of time than, for example, iron gluconate or iron sucrose, 30 Higher single unit doses can result in the need for fewer injections to replete iron stores, and consequently is often better suited for outpatient use. [00681 After intravenous administration, the Iron carboxymaltose complex (e.g,, VIT 45) is mainly found in the liver, spleen, and bone marrow. Pharmacokinetic studies using positron emission tomography have demonstrated a fast Initial elimination of radioactively labeled 35 iron (Fe) "Fe"PFe VIT~45 from the blood, with rapid transfer to the bone marrow and rapid deposition in the liver and spleen. See e.g. Beshara et alt (2003) Br J Haematol 2003; 120(5): 853-859. Eight hours after administration,5 to 20% of the injected amount was observed to be '4 still in the blood, compared with 2 to 13% for iron sucrose, The projected calculated terminal half-life (t.) was approximately 16 hours, compared to 3 to 4 days for iron dextran and 6 hours for iron sucrose. [0 069 The iron in the iron carboxyrnaltose complex (e.g, VITAS) slowly dissociates 5 from the complex and can be efficiently used in the bone marrow for Hgb synthesis. Under VIT 45 administration, red cell utilization, followed for 4 weeks, ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems, Thus, high red cell utilization of iron carboxymaltose complex occurs in anemic patients. In addition, the reticuloendothelial uptake of this complex reflects the safety of , 10 polysaccharide complexes, Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool (eg, transferrin). [00701 Other studies in patients with iron deficiency anemia revealed increases in exposure roughly proportional with VIT-45 dose (maximal total serum iron concentration was approximately 150 pg/mL. and 320 pg/mL following 500 mg and 1000 mg doses, respectively), in I5 these studies, VIT-45 demonstrated a monoexponential elimination pattern with a ti in the range 7 to 18 hours, with negligible renal elimination. [0071) Single-dose toxicity studies have demonstrated safety and tolerance in rodents and dogs of intravenous doses of an iron carboxymaltose complex (VIT-45) up to 60 times more than the equivalent of an Intravenous infusion of 1,000 mg iron once weekly in 20 humans, Pre-olinical studies in dogs and rats administered VIT-45 in cumulative doses up to 117 mg iron/kg body weight over 13 weeks showed no observed adverse effect level In dose-related clinical signs of iron accumulation in the liver, spleen, and kidneys. No treatment-related local tissue irritation was observed in intra-arterial, perivenous, or intravenous tolerance studies in the rabbit, In vitro and in vivo mutagenicity tests provided no evidence that VIT-45 is clastogenic, 25 mutagenic, or causes chromosomal damage or bone marrow cell toxicity, There were no specific responses to VIT-45 in a dextran antigenicity test. [0 072] Approximately 1700 subjects have been treated with an iron carboxymaltose complex (VIT-45) in open label clinical trials (see e,g, Example 5). Many of these subjects have received at least one dose of 15mg/kg (up to a maximum dose of 1,000 mg) of VIT-45 over 15 30 minutes intravenously. Few adverse events and no serious adverse events or withdrawals due to adverse events related to VIT-45 administration have been reported. No clinically relevant adverse changes in safety laboratories have been seen. [00733 The physicochemical characteristics of the iron carboxymaltose complex (eg., VIT-45), the patten of iron deposition, and the results of the above described studies 3S demonstrate that iron carboxymaltose complex can be safely administered at high single unit therapeutic doses as described herein, [0 07 4] Polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite [0 075) Another preferred iron carbohydrate complex for use in the methods described herein is a polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite (eg, "ferumoxytol"). Ferumoxytol is known in the art to be effective for treating anemia (at single unit 5 doses lower than described herein). See eg., Spinowitz et alt (2005) Kidney Intl 68, 1801-1807. Ferumoxytol Is a superparamagnetic iron oxide that is coated with a low molecular weight semi synthetic carbohydrate, polyglucose sorbitol carboxymethyl ether. Ferumoxytol and its synthesis are described in US, Patent No. 6,599,498, incorporated herein by reference, Safety, efficacy, and pharmacokinetics of ferumoxytol are as described, for example, in Landry et al (2005) Am J 10 Nephrol 25,400-410, 408; and Spinowitz et al (2005) Kidney Intl 68, 1801-1807, tO0763 The iron oxide of ferumoxytot is a superparamagnetic form of non stoichiometric magnetite with a crystal size of 6,2 to 7.3 nma. Average colloidal particle size can be about 30 nm, as determined by light scattering. Molecular weight is approximately 750 RD, The osmolarity of ferumoxytol is isotonic at 297 mOsm/kg and the pH is neutral, The blood half 15 life of ferurnoxytol is approximately 10-14 hours. It has been previously reported that ferumoxytol can be given by direct intravenous push over 1-5 minutes in doses up to 1,800 mg elemental iron per minute, with maximal total dose up to 420 mg per injection. Landry et al (2005) Am J Nephrol 25, 400-410, 408, (00771 Core and Particle Size 20 £0078] intravenous iron agents are generally spheroidal iron-carbohydrate nanoparticles. At the core of each particle is an iron-oxyhydroxide gel. The core Is surrounded by a shell of carbohydrate that stabilizes the iron-oxyhydroxide, slows the release of bioactive iron, and maintains the resulting particles in colloidal suspension. Iron agents generally share the same core chemistry but differ from each other by the size of the core and the identity and 25 the density of the surrounding carbohydrate. See Table 1; Figure 1. - 16- Table 1: Core and Particle Size of Iron Carbohydrate Complexes Iron (111) Control Release Test Size of the Particle (nm) +/- SEM
T
7 s (min) Iron core Total Particle Dexferrum (an iron dextran) 122.5 J 1 ± 4 27 ± 6 VIT -45 (an iron carboxymaitose) 117.8 44 4A14 &.7t 2,5 Venofer (an iron sucrose) 10,2 28±1 5 i 4 toois9 Differences in core size and carbohydrate chemistry can determine pharmacological and biological differences, including clearance rate after injection, Iron release rate in vitro, early evidence of iron bioactivity in vivo, and maximum tolerated dose and rate of 5 infusion. E oCoQo One of the primary determinants of iron bloactMty is the size of the core and the surface area to volume ratio, Generally, the rate of labile iron release in each agent is inversely related to the size of its iron core, Van Wyck (2004) J. Am, Soc. Nephrology 15, S107 Si$11,1 S109. Furthermore, in vitro iron donation to transferrin is inversely related to core size, 0 Core size can depend upon the number of iron atoms contained within, For example, the number of Iron atoms contained within a I nm core is calculated to be 13, while a 10 nm cores calculated to contain 12770 iron atoms. Where agents share the same core chemistry. the rate of iron release per unit surface area is likely similar, differing perhaps by the strength of the carbohydrate ligand-core iron bound, But for the same total amount of core iron, surface area 15 available for iron release increases dramatically as core radius decreases. That is to say, for equal amounts of iron, the smaller the core, the greater the surface area available for iron release. Of course, the explanation for this non-linear trend is the fact that volume is radius cubed, In short, a collection of many small spheres exposes a greater total surface area than does a collection of an equal mass of fewer, larger spheres, 20 [08o21 A smaller iron core size of an iron complex administered for the treatment of various diseases, disorders, or conditions allows wider distribution through tissues, a greater rate of labile iron release, and increased in vitro iron donation to transferrin. Furthermore, the iron complex is more evenly distributed and metabolizes faster due to the smaller core size. But if the core size is too small, the iron complex can move into cells unable to metabolize iron. In one 25 embodiment, an iron complex with a mean iron core size of no greater than about 9 nm is administered, In various embodiments, mean iron core size is less than about 9 nm but greater than about I nm, about 2 nm, about 3 nr, about 4 nrm, about 5 nm, about 6 nm, about 7 nm, or about 8 nrn, Mean iron core size can be, for example, between about I nm and about 9 nra; between about 3 nm and about 7 nm; or between about 4 nrm and about 5 im. 5 [00821 The molecular weight (Le,, the whole molecular weight of the agent) is considered a primary determinant in the pharmacokinetics, or in other words, how quickly it is cleared from the blood stream. The amount of labile (ie,, biological available) iron is inversely correlated with the molecular weight of The iron-carbohydrate complex. Van Wyck (2004) J. Am. Soc. Nephrology 15, S107-S 111, S 109, That is to say, the magnitude of labile iron effect Is to greatest In Iron-carbohydrate compounds of lowest molecular weight and least In those of the highest molecular weight. Generally, there is a direct relationship between the molecular weight of the agent and the mean diameter of the entire particle (ie, the iron core along with the carbohydrate shell). In various embodiments, the mean diameter size of a particle of the Iron carbohydrate complex is no greater than about 35 nm, For example, the particle mean size can IS be no greater than about 30 nm, As another example, the particle mean size can be no greater than about 25 nrm, As another example, the particle mean size can be no greater than about 20 nim. As another example, the particle mean size can be no greater than about 15 nm. As a further example, the particle mean size can be no greater than about 10 nrn. As another example, the particle mean size can be no greater than about 7 nm, 20 100o Absence of Significant Adverse Reaction to the Single Dosage Unit Administration [00841 Generally, a safe and effective amount of an iron carbohydrate complex is, for example, that amount that would cause the desired therapeutic effect In a patient while minimizing undesired side effects. The dosage regimen will be determined by skilled clinicians, 25 based on factors such as the exact nature of the condition being treated, the severity of the condition, the age and general physical condition of the patient, and so on, Generally, treatment emergent adverse events will occur in less than about 5% of treated patients. For example, treatment-emergent adverse events will occur In less than 4% or 3% of treated patients. Preferably, treatment-emergent adverse events will occur in less than about 2% of treated 30 patients. 1oo85 For example, minimized undesirable side effects can include those related to hypersensitivity reactions, sometimes classified as sudden onset closely related to the time of dosing, including hypotension, bronchospasm, layngospasm, angioedema or uticaria or several of these together. Hypersensitivity reactions are reported with all current intravenous iron 35 products independent of dose. See generally Batle et at (2005) Nephrol Dial Transplant, 20(7). 1443-1449. As another example, minimized undesirable side effects can include those related to labile iron reactions, sometimes classified as nausea, vomiting, cramps, back pain, chest pain, and/or hypotension, Labile iron reactions are more common with Iron sucrose, iron gluconate, and Iron dextran when doses are large and given fast. £00861 Pharmaceutical Formulations £00871 In many cases, a single unit dose of Iron carbohydrate complex may be 5 delivered as a simple composition comprising the iron complex and the buffer in which it is dissolved. However, other products may be added, if desired, for example, to maximize iron delivery, preservation, or to optimize a particular method of delivery. £00 S 51 A pharmaceuticallyy acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and anti-fungal agents, Isotonic and absorption delaying 10 agents, and the like, compatible with pharmaceutical administration (see e.g., Banker, Modem Pharmaceutics, Drugs and the Pharmaceutical ScIences, 4th ed, (2002) ISBN 0824706749; Remington The Science and Practice of Pharmacy, 21st ed. (2005) ISBN 0781746736), Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Fingers solutions and dextrose solution. Supplementary active compounds can also be I Incorporated into the compositions. For intravenous administration, the iron carbohydrate complex is preferably diluted in normal saline to approximately 2-5 mg/ml The volume of the pharmaceutical solution is based on the safe volume for the Individual patient, as determined by a medical professional £0089 An iron complex composition of the invention for administration is formulated 20 to be compatible with the intended route of administration, such as intravenous injection. Solutions and suspensions used for parenteral, intradermal or subcutaneous application can include a sterile diluent, such as water for injection, saline solution, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; buffers such 25 as acetates, citrates or phosphates, and agents forte adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Preparations can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. [00 901 Pharmaceuticai compositions suitable for injection include sterile aqueous 30 solutions or dispersions for the extemporaneous preparation of sterile Injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL" (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). The composition must be sterfile and should be fluid so as to be administered using a syringe. Such compositions should be stable during manufacture and storage and must be 35 preserved against contamination from microorganisms, such as bacteria and fungi. The carrier can be a dispersion medium containing, for example, water, polyot (such as glycerol, propylene glycol, and liquid polyethylene glycol), and other compatible, suitable mixtures, Various - 19antibacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosa, can contain microorganism contamination, Isotonic agents such as sugars, polyalcohols, such as manitol, sorbitol, and sodium chloride can be included in the composition. Compositions that can delay absorption include agents such as aluminum monostearate and 5 gelatin. [0091] Sterile injectable solutions can be prepared by incorporating an Iron complex in the required amount in an appropriate solvent with a single or combination of ingredients as required, followed by sterilization. Methods of preparation of sterile solids for the preparation of sterile injectable solutions include vacuum drying and freeze-drying to yield a solid containing the 10 iron complex and any other desired ingredient, (00921 Active compounds may be prepared with carriers that protect the compound against rapid elimination frorn the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable or biocompaible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, 1' polyorthoesters, and polytactic acid. Such materials can be obtained commercially from ALZA Corporation (Mountain View, CA) and NOVA Pharmaceuticals, Inc, (Lake Elsinore, CA), or prepared by one of skill in the art, [00931 A single unit dose of iron carbohydrate complex may be intravenously administered in a volume of pharmaceutically acceptable carrier of, for example, about '1000 mg 20 of elemental iron in about 200 ml to about 300 ml of diluent. For example, a single unit dose of iron carbohydrate complex may be intravenously administered in a volume of pharmaceutically acceptable carder of about 1000 mg of elemental iron in about 250 m" of diluent, As another example, a single unit dose of iron carbohydrate complex may be intravenously administered in a volume of pharmaceutically acceptable carrier of about 1000 mg of elemental iron in about 215 25 ml of diluent. [00943 A preferred pharmaceutical composition for use in the methods described herein contains VIT-45 as the active pharmaceutical ingredient (API) with about 28% weight to weight (rn/mn) of iron, equivalent to about 53% /rm iron (l11)-hydroxide, about 37% m/m of fIgand, 56% rn/m of NaCI. and 51 0% mn/mn of water. 30 [ 095] TKits for pharmaceutical compositions 0 0961 Iron complex compositions can be included in a kit container, pack or dispenser, together with instructions for administration according to the methods described herein, When the invention is supplied as a kit, the different components of the composition may be packaged in separate containers, such as ampules or vials, and admixed immediately before 35 use. Such packaging of the components separately may permit long-term storage without losing the activity of the components, Kits may also include reagents In separate containers that facilitate the execution of a specific test, such as diagnostic tests. [00973 The reagents included in kits can be supplied in containers of any sort such that the life of the different components are preserved and are not adsorbed or altered by the 5 materials of the container. For example, sealed glass ampules or vials may contain lyophilized iron complex or buffer that have been packaged under a neutral non-reacting gas, such as nitrogen. Ampules may consist of any suitable material, such as glass, organic polymers, such as polycarbonate, polystyrene, etc, ceramic, metal or any other material typically employed to hold reagents. Other examples of suitable containers include bottles that are fabricated from 10 similar substances as ampules, and envelopes that consist of foil-lined interiors, such as aluminum or an alloy. Other containers include test tubes, vials, asks, bottles, syringes, etc Containers may have a sterile access port, such as a bottle having a stopper that can be pierced by a hypodermic injection needle. Other containers may have two compartments that are separated by a readily removable membrane that, upon removal, permits the components to mix. 1 Removable membranes may be glass, plastic, rubber, etc. [0 0983 Kits may also be supplied with instructional materials, instructions may be printed on paper or other substrate, and/or may be supplied on an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, mIni-disc, SACD, Zip disc, videotape, audio tape, etc, Detailed instructions may not be physically associated with the kit; instead, a user may be 20 directed to an intemet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mal. [0 0993 Having described the invention in detall, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing the scope of the invention defined in the appended claims, It should be understood that all references cited are 25 incorporated herein by reference. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples. EXAMPLES [010 03 The following non-limiting examples are provided to further illustrate the present invention, It should be appreciated by those of skill in the art that the techniques 30 disclosed in the examples that follow represent approaches the inventors have found function well in the practice of the invention, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made In the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. - 21 - Example 1: Non-ToxicIty Studies [0101) Nonclinical toxicity of VIT-45 is very low, as is normal for Type i polynuclear iron (l1)-hydroxide carbohydrate complexes. The single dose toxicity is so low that the LDr could not be estimated and is higher than 2000 mg iron/kg b.w. Mice tested with a single dose of $ 250 mg iron/kg b.w., injected within 2 seconds, showed no signs of illness, The highest non lethal dose level of 1000 mg iron/kg b.w. in mice and rats is also very high in comparison to a single unit dose of, for example, 15 mg iron/kg b.w. once per week in humans, These results provide factors of about 70-fold a human dose, demonstrating a large safety margin for acute toxicity of the product, 10 Example 2: Pharmokinetic Studies [0102) }Pharmacokinetic and red blood cell measurements of "Fel"Fe labelled VIT 45 following i,v, administration using PET In 6 patients showed a red blood cell utilization from 61 to 99%. The 3 patients with iron deficiency anemia showed a utilization of radiolabelled iron of 91 to 99% after 24 days, compared to 1 to 84% for 3 patients with renal anaemia, The terminal t, iS for VIT-45 was calculated to be approximately 16 hours, compared to about 6 hours for iron sucrose. In two further studies in patients with iron deficiency anemia, pharmacokinetic analyses revealed increases in exposure roughly proportional with VIT-45 dose (Cmax approximately 150 pg/mL and 320 pg/mL following 500 mg and 1000 mg doses, respectively), VIT-45 demonstrated a monoexponential elimination pattem with a t 1 , in the range 7 to 18 hours. There was negligible 20 renal elimination Example 3: Efficacy Studies (0103) The main pharmacodynamic effects of VIT-45 were transient elevations of serum iron levels, TfS and serum ferritin, These effects were seen in all studies (where measured), following both single doses and repeated doses, The increase in serum ferritin levels 25' Illustrated the replenishment of the depleted iron stores, which is a well-Identified and desired effect of iron therapy. In addition, transiently elevated TfS indicated that iron binding capacity was almost fully utilized following VIT-45 infusion. [0104) Efficacy of iron replacement therapy is interpreted mainlyin terms of the ability to normalise Hb levels and iron stores, In the multiple dose studies, patients demonstrated a 30 slowly-developing, sustained increase in Hb levels during study participation. In one study, 37% and 48% of patients in Cohorts I and 2, respectively, had achieved normal Hb levels at the 4 week follow-up visit, and 75% and 73%, respectively, had achieved a 220 g/L increase in Hb on at least I occasion. [OiOS) In another study (patients receiving regular haemodialysis), the majority of 3$ patients (61,7%) achieved an increase of Hb of a1 0 g/L at any point during the study. Serum ferritin and TfS levels showed a more prolonged elevation following repeated VIT-45 infusions, indicating a sustained replenishment of iron stores, Howeiter, elevated levels of ferritin and TfS indicating iron overload were avoided. In both of these studies, there was a gradual decrease in transferrin over time, also indicating successful iron replacement Example 4: Safety Assessments 5 [010 Safety assessments were made in 73 patients with iron deficiency anemia (27 single-dose, 46 repeated-dose), and 166 patients with renal anemia (3 single-dose, 163 repeated-dose) who received VIT-45 at individual iron doses of 100 mg up to 1000 mg (cumulative doses of 100 to 2200 meg). These studies showed a safety profile equal to, or exceeding, currently available parenteral iron formulations, 10 0107) in the single-dose studies, there were few adverse events and no serious adverse events or withdrawals due to adverse events, There were also no related clinically relevant adverse changes in vital signs, 12-lead ECGs or laboratory safety tests. [010 ) in the repeated-dose studies, there were no deaths attributed to VIT-45, while 10 patients experienced serious adverse events. All of these cases occurred in patients with 15 renal anaemia receiving haemodialysis and were considered not related to the VIT-45 treatment. Very few patients were withdrawn from the studies due to treatment-emergent adverse events, and only 2 withdrawals (due to allergic skin reactions) were considered possibly related to treatment. In each of the repeated-dose studies, no patients experienced clinically significant changes in 12-lead ECGs that were related to treatment. There were no consistent changes in 20 laboratory safety parameters, although there was a low incidence (total 6 patients) of laboratory values reported as treatment-related treatment-emergent adverse events (elevated CRP, AST, ALT and GGT, abnormal liver function tests and elevated WBC). [010 93 Although many patients in these 2 studies had serum ferritin above 500 pg/L on at least I occasion during the study, very few patients also had TfS values >50%, Generally, 25 the elevations of ferritin and TfS were of short duration. Iron overload was avoided using the dosing schedules defined in the studies, Example 5: Integrated Safety Studies [01101 The following example demonstrates the safety and effectiveness of parenteral VIT-45 in the treatment of anemia in a variety of patient populations, as determined 30 from several integrated safety studies. (0111] A total of 2429 subjects were treated with ViT-45 or control agents oyer 10 studies that provide safety date for VIT-45. Of these, 1709 subjects received VIT-46 (1095 in completed multicenter studies, 584 in placebo-controlled, single-dose, crossover studies and 30 in pharmacokinetic studies). The mean total dose of VIT-45 administered among the 35 1095 subjects in the completed multicenter studies was approximately 1300 mg; however, some subjects receIved VIT-45 doses as high as 3400 mg. The majority of the subjects treated were able to receive their calculated iron requirement in only 1 or 2 doses. (01121 Table 2 provides a summary of VIT-45 studies described in this example, [01131 Study A was a single-center, single-dose escalation, randomized, double 5 blind, placebo-controlled pharmacokinetic study, Subjects were male and female, between 18 and 45 years of age, inclusive, with mild iron-deficiency anemia. Treatment was a single IV bolus Injection of VIT-45 at 100 mg, 500 mg, 800 mg, or 1000 mg. Examined pharmacokinetic parameters included total serum iron and pharmacodynarnic (serum ferritin and transferrin, iron binding capacity, %TSATpost, hemoglobin, reticulocyte, and serum transferrin receptor 10 concentrations) endpoints. Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, ECG, and physical examinations. [01141 Study B was a single-center, single-dose, open label, uncontrolled pharmacokinetic study. Subjects were between 18 and 75 years of age with Iron-deficiency or renal anemia with no other cause of anaemia. inclusion criteria included hemoglobin 1s concentration between 9 and 13 g/dL, no blood transfusions in the previous 3 months, and no history of treatment with Intravenous iron in the last 2 weeks. Treatment was a single IV bolus injection of VIT-45 at 1 00 mg labelled with 5 "Fe and "Fe. Examined primary pharmacokinetic parameters included the distribution of 2 Fe and incorporation of "Fe into red blood ces, Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, 20 and physical examinations, [015l s) Study C was an open-label, multicenter, randomized, multiple-dose, active controlled postpartum anemia study. Subjects were female, postpartum within 10 days after delivery, with hemoglobin 510 g/dL at Baseline based on the average of 2 hemoglobin values drawn 18 hours postpartum. Treatment was once weekly doses of VIT-45 for six weeks, VIT 25 45 dosage was based on the caidulated iron deficit ( 2500 mg total). Where screening serum transferrin saturation (TSAT) was 20% or screening ferritin was 50 nglmL, dosage = pre pregnancy weight (kg) x (15-baseine hemoglobin {g/dLl) x 2.4 + 500 mg. Where screening TSAT was >20% and screening ferritin was >50 ng/mL, dosage = pre-pregnancy weight (kg) x (15-baseline hemoglobin [g/dLJ) x 2.4, Infusion of VIT-45 was as follows: 200 mg, administered 30 as an undiluted intravenous push (IVP) over 1-2 minutes; 300-400 mg, administered in 100 cc normal saline solution (NSS) over G minutes; 500-1,000 rq administered in 250 cc NSS over 15 minutes. Por primary efficacy, "success' was defined as an increase in hemoglobin of a2 g/dL anytime between baseline and end of study or time of intervention, while 'faIlure was defined as <2 g/dL increase in hemoglobin at all times between baseline and end of study or time of 35 intervention, Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, and physical examinations. -24 - (01163 Study ID was a multicenter, open-label, randomized, active-controlled, multiple dose postpartum anemia study. Subjects were adult women -18 years old with postpartum anaemia wIthin 6 days after delivery- Treatment was administered once-weekly for a maximum of 3 infusions. Patients received IV infusions of 16,7 mL/min to deliver a maximum dose of 1000 5 mg iron per infusion. Patients received VIT-45 infusions once weekly for up to 3 occasions until the calculated cumulative dose was reached. Patients s66 kg received a minimum dose o 200 mg and a maximum dose of 15 my iron/kg during each infusion, Patients >66 kg received a dose of 1000 mg on the first dosing occasion, and a minimum dose of 200 mg and a maximum dose of 1000 mg at each subsequent dosing, Doses of 200-400 mg were diluted in 100 cc NSS and 10 500-1000 mg were diluted in 250 cc NSS. Primary efficacy was examined as change from baseline levels of hemoglobin to Week 12, Examined safety parameters included adverse events in the mother and breast-fed infant, adverse events leading to discontinuation of treatment, vital signs, 12-lead electrocardiogram (ECG), physical examinations, and clinical laboratory panels, 15 [0117) Study E was a multicenter, open-label, randomized, active-controlled, multiple dose hemodatysis-associated anemia study, Subjects were adult maie or female subjects between the ages of 18 and 80 years (inclusive) requirIng haemodialysis with iron deficiency secondary to chronic renal failure. Dosing started on Day 1, Week 0 for both treatment arms and continued 2 or 3 times weekly until the indivdual calculated cumulative dose was reached, 20 Patients received 200 rmg VIT-45 during their scheduled haemodialysis sessions (2-3 sessions/week) until the calculated cumulative dose was reached, Cumulative total iron requirement was calculated for each patient using the Ganzoni formula. Primary Efficacy was examined as the percentage of patients reaching an Increase in hemoglobin 10 g/L at 4 weeks after baseline. Examined safety parameters included adverse events, vital signs, 12-lead EGG, 25 physical examinations, and clinical laboratory evaluations. [oaa8e Study F was a multicenter, open-label, multiple dose, uncontrolled hemodialysis-associated anemia study. Subjects were male and female patients 18-65 years of age, inclusive, with haemodialysis-associated anaemia undergoing maintenance haemodialysis, Treatment duration was a maximum of six weeks, Patients received 200 rmg VIT-45 during their 30 scheduled haemodialysls sessions (2-3 sessions/week) until the calculated cumulative dose was reached. Cumulative total iron requirement was calculated for each patient using the Ganzoni formula. Efficicacy was examined as correction of iron deficiency and hemoglobin concentration of the patient. Examined safety parameters included adverse events, vital signs, 12-lead ECG, physical examinations, haematology and blood chemistry profiles, and urea reduction ratio. 35 [0o119) Study G was a multicenter, multiple-dose open-label, uncontrolled gastrointestinal disorder-associated anemia study, Subjects were males and females between 18 and 60 years of age, inclusive, wIth moderate stable iron-deficiency anemia secondary to a -25gastrointestinal disorder and a calculated total iron requirement 1000 mg; 50% of patients in each cohort were to require 1500 mg total iron, Duration of treatment was single doses at weekly intervals for up to 4 weeks (Cohort 1) or 2 weeks (Cohort 2). Administration of VIT-45 was by IV bolus injection of 500 mg (Cohort 1) or 1000 mg (Cohort 2), where total iron 5 requirement for each patient, which determined how many weekly infusions were received, was calculated using the formula of Ganzoni, Examined pharmacokinetic parameters included total serum iron and pharmacodynamic (hemoglobin, ferritin, TSAT) endpoints. Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, EGG, physical examinations, and elevated serum ferritin (>500 igL) AND elevated TSAT (>45%). 10 [0120] Study H was a multicenter, multiple-dose randomized, open-label, active-controlled gastrointestinal disorder-associated anemia study, Subjects were males and females aged 18 to 80 years, inclusive, with iron-deficiency anaemia secondary to chronic inflammatory bowel disease (ulcerative colitis or Crohn's disease) and a calculated total iron requirement of at least 1000 mg total iron, Treatment was weekly VIT-45 infusions, with a 15 maximum of 3 infusions pemiitted in a single treatment cycle. Administration consisted of an infusion on Day 1, with subsequent infusions at weekly intervals up to a maximum of 1000 mg iron per dose. The doses were continued until the patient received the cumulative dose based on their individual requirement for iron. Primary efficacy was examined as change from baseline to Week 12 in hemoglobin. Examined safety parameters included adverse events, vital signs, 20 12-lead ECG, physical examinations, and clinical laboratory evaluations, [0121] Study I was an open label, multiple-dose, multicenter, randomized, active control anemia due to heavy uterine bleeding study. Subjects were females at least 18 years of age with iron-deficiency anemia secondary to heavy uterine bleeding, Duration of treatment was six weeks. VIT-45 dosage was based on the calculated iron deficit as follows: where baseline 25 TSAT 20% or baseline ferritin 50 ng/mL, VIT-45 total dose In mg = baseline weight (kg) x (15 baseline hemoglobin [g/dM.) x 2.4 + 500; where baseline TSAT >20% and baseline ferritin >50 ng/mL, VlT-45 total dose in nig = baseline weight (kg) x (15-baseine hemoglobin [g/dLj) x 2.4. For administration, 200 mg was administered as an undiluted IVP over 1-2 minutes; 300-400 mg was administered in 100 cc NSS over 6 minutes; and 500-1,000 mg was 30 administered in 250 cc NSS over 15 minutes. Primary efficacy was examined as the proportion of subjects achieving success, defined as an increase in hemoglobin of 2,0 g/dL anytime between baseline and end of study or time of intervention, Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, and physical examinations. [01221 Study J was a multicenter, single-dose bijnded, randomized, placebo 35 controlled crossover iron deficiency anemia study, Subjects were male or female, at least 18 years of age, with a hemoglobin 12 g/dL, TSAT 25%, and ferritin <300 ng/mL (iron deficiency anemia due to dialysis or non-dialysis dependent chronic kidney disease or irflammatory bowel disease), or ferritin s100 ng/m L (iron-deficiency anemia due to other conditions). Treatment was two single doses seven days apart. Administration of ViT-45 occurred over 15 minutes and was 1000 mg (15 mg/kg for weight 566 kg). For pharmacokinetic variables, total serum iron was assessed using Atomic Absorption methodology. Examined 5 safety parameters Included adverse events, clinical laboratory evaluations, vital signs, and physical examinations. TABLE 2: Summary of Safety Studies of VIT-45 Study Number Subjects Intravenous Dose(s) orvlT-4 Comparator Phrmacolinere Studies A Total: 32 Single doses of: Placebo VFA: 24 100 Og via bolos injection 300mg,800 mg. i000rpu diluted in 250 mL of NoS adminiered by W ifsion over 15 rIn ste tuesin su~u' etsar-nemi 13 Total, 6 Sing dose or100 mg abeled wis Fe and Fe None VY 45:4 6 administered s an IV InRetion over 0flamises C Total: 352 Cumulative total iron reqluiremem was calculated Oral iron (rsous VlT-45; 17l4 for each patient Padetrs received IV lnfissons to suite) 325 mag TID [deliver a maximum dose of 1000 mg iron per far 6 weeks Patients received VIT-45 infusions once weekly utlhie calculated cumulative dose waes reached or a maxinmum ofr2500 rmg had been admiistered. Doses s200 mag were administered V push over -2 minutes; domes o300,400 mg werm dilted in 100 cc NSS ard admi;islered over 6 minutes; doses of 500-1000 Gg wem di led in 250 cc NSS and administered over iS minutes D otala44 Cumulative total iron requirement was calri asd Oral iron (feous vf45: 227 for each patient using the Canzoni formula, sulfare3 100 mag .01D for 12 weeks Studies in Subjects Undergoing flemodialysis Total 237 MPadens received 200 og IV bolos injection of Venol?* patients V 4T-5P i 11) study drug during theircheduld hemodlalysie received 200 mg IV facsaiona (23 aeassonsheek) until the eniuened injection ove 10 (eunusative dose was reached. Cumulative total minutes of study u-en requtirement was calculaed for each patient drug during their using the'Gnanaoni formula, scheduled lrcmodiatysis sessions (13 sessions/weck) unmil the eaindalted -cumutktive dose was reoched- Curiltive totaO iron req~uiremsent was~ ccuated for each patient using the mnzn anmuda? F Toal: 351 Patients received 200 mg WV push ofat udy drug None V62 during their scheduled henmodielysis sessions (2 3 sessions/week) until the calculated cuativea Dose was reached Cumulative total iron requirement was calculated for each patient using the Garoi formula Studies in subjects with Castraintetlinal Disorders __________ _________ G Totab: 46 500 eMg or 1000 mag iron by 19 infusion at weekly None ViT45: 46 Intervas 1r up to 4 weeks (00 mg)or 2 weeka (!00 tug); nsssnm total dose oC2000 nti, The last doe could have been less, depending onr tihe caictlated toin iron requirement Doses were diluted in 250cc NSS end administered by Av fusion over 5 minutes. N Total 200 cumualive total iron requirement was calulated or iron ( wrrous VIT-45: 13 for each patient using the Ganeoni formula, Isulthe) 100 mg B1D ____________I ________ fr 12 weeks study in subjects wilk Heavy Uterdne Bleeding Toalh: 46 1000 rMg/week (5 mg/kg for weighs si66 kg Orairon (rrous vlT'45: 230 patients received viTA5 inrsIsm once weekly safhe) 325 mgTtD until te calculated cumulative dose was reached or for 6,weks a maimum or200 mtg had been administered, Does 200 mg were adminstered IV push over 1 l00 e NSs andtanisere over 6minus; doses or minutes; mgere f 300ed rg wee diluted ind Study in Subjects with iron Deficiency Anemia S ~Total: 504 jSigle dose efslQO0 mag by Iv infusion over IS Prlaceb~o VIT$ 584 4nucs (15 mgikg for weight66 kg). Doses 500 myg were diutted in l00 4c NSS and doses or j>SO00-000 mg rdiksued in 250 cc 43N , Phtanacokinedie subjects single 1,00 mag dose by Iv infusion CO 123)l The majority of the subjects who received VIT~45 completed the study. The incidence of premature discontinuations in the completed multicenter studies was 10% in the ViT-45 group which is comparable to that observed in the oral iron (9.6%) and Venofer (13,6%) groups, Reasons for premature discontinuation were generally comparable among the treatment 5 groups, except that the incidence of adverse events leading to discontinuation were higher in the Venofer group (5,9%/) compared to the VIT-45 (1.8%) and ora! iron (2.1%) groups, demonstrating the overall tolerability of VIT-45. [0124] The overall incidences of treatment-emergent adverse events were comparable between the VIT-45 (49,5%) and oral Iron (51.2%) groups in the completed t0 multicenter studies; the incidence in the Venofer group was lower (39,0%): however, the number of subjects in the VIT~45 group is almost 10-fold that of the Venofer group, Treatment-emergent adverse events e xperienced by 2% of the 1095 VIT-45 subjects included headache (8.6%), abdominal pain (2.5%), nausea (2,4%), blood phosphate decreased (2A4%), hypertension (2.2%), nasopharyngitis (2,0%), and hypotension (2,0%). As expected, the most notable difference 15 between subjects treated with VIT-45 and those treated with oral iron was for the incidence of gastrointestinal events (31.0% vs, 12.8%), specifically the incidences of constipation, diarrhea nausea, and vomiting, which were more than double that observed In the VIT-45 group, [012 51 In the calculated dose/first-dose 1,000 mg studies, no statistically significant difference was observed between the VIT-45 (49,5%) and oral iron (51.2%) groups for the overall 20 Incidence of treatment-emergent adverse events. The incidence of gastrointestinal disorders - 2$ was statistically significantly (p<0,O001) higher in the oral iron group (31,0%) compared to the VIT-45 group (15,2%), while the incidences of adverse events associated with investigations and skin and subcutaneous tissue disorders were statsticaly significantly higher in the ViT-45 group (9.1% and 7,3%, respectively) compared to the oral iron group (3,9% and 2.4%, respectively). 5 Among the gastrointestinal disorders, greater proportions of subjects in the oral iron group than the VIT-45 group experienced constipation, nausea, diarrhoea, and vomiting, while a greater proportion of VIT-45 subjects experienced abdominal pain than oral iron subjects. Among the adverse events associated with investigations, greater proportions of VIT-45 subjects experienced blood phosphate decreased and GGT increased than oral iron subjects. Among the 10 adverse events associated with skin and subcutaneous tissue disorders, greater proportions of VIT-45 subjects experienced rash and pruritus than oral iron subjects. [0125 6The only drug-related treatment-emergent adverse events reported by at least 2% of VIT-45 subjects in the calculated doselfirst-dose 1,000 mg studies were headache (3.9%) and blood phosphate decreased (3.3%), The incidence of treatment-emergent adverse events !5 reported on the first day of dosing In the calculated dose/first-dose 1,000 mg studies was statistically significant higher in the VIT4 group compared to the oral iron group (6,8% vs. 2.7%) On the first day of dosing, the VIT-45 group had statistically significantly greater proportions of subjects who experienced general disorders and administration site conditions, primarily events associated with the site of study drug infusion, and skin and subcutaneous 20 issue disorders, primarily rash and urticaria, compared to the oral Iron group, [0127) The overall incidence of treatment-emergent adverse events was similar among VIT-45 subjects treated with either the 200 mg or 1000 mg doses. The only notable difference was for the higher incidence of headache in the 1000-mg group, which was almost double that observed for the 200-mg group. No meaningful trends were apparent with respect to 25 the incidence of treatment-emergent adverse events when analyzed by gender, age, race, weight, or etiology of anemia, [01281 There were no deaths in the study attributed to VIT-45, The incidence of other serious adverse events among VIT-45 subjects was low (3% In all completed multicenter studies and 0.3% in the placebo-controlled, single-dose crossover study) and none were considered 30 related to study drug. The incidence of premature discontinuation due to adverse events was comparable between the VIT-45 group (2,1%) and the other active treatment groups (3.1% oral iron And 2,5% Venofer), The incidence of drug-related treatment-emergent adverse events of hypersensitivity was 0.2%, the same as that observed with oral iron (0.2%). Drug-related mild or moderate hypotension was observed in 4 (0.2%) VIT-45 subjects, none of which were 35 considered serious, led to premature discontinuation, or were symptomatic. Treatment-emergent adverse events indicative of potential allergic reactions including rash, pruritus, and urticaria - 29 were reported by <2% of subjects who were treated with VIT-45; none of these events was considered serious and few led to premature discontinuation [0129) Laboratory evaluations of mean changes from baseline and potentially clinically significant values demonstrated no clinically meaningful changes for the majority of the 5 parameters evaluated, However, during the conduct of the latter portion of the clinical program, transient, asymptomatic decreases in blood phosphate levels were observed among subjects treated with VIT-45. The decreases were apparent approximately 7 days after the initial dose of VIT-45 and the median time to recovery was approximately 2 weeks No subjects reported an adverse event that was related to serum phosphate and no subject discontinued front the study 10 due to decreased serum phosphate, The only predictor of change in serum phosphate was that subjects with higher baseline serum phosphate values had larger decreases in serum phosphate. The fact that the majority of oral Iron-treated subjects also had a post-baseline decrease in phosphate and the negative correlation of baseline serum phosphate with changes in serum phosphate for both the VIT-45 and oral iron treatment groups suggest that the mechanism is 15 intrinsic to iron therapy in this severely anemic population, [0301 Overall, no clinically meaningful changes in vita& signs evaluations were associated with VIT45 administration. (01311 Safety data from more than 1700 subjects demonstrate the safety and tolerability of VIT-45. [0l32] A reference herein to a patent document or other matter which is given as prior an is not taken -as an admission that that document or prior art was part of common general knowledge at the priority date of any of the claims. [0131 With reference to the use of the word(s) "comprise" or "comprises" or "comprismg" in the foregomg description and/or i the following claims, unless the context requires otherwise, those words are used on the basis and clear understand that they are to be interpreted inclusively. ruler than exclusively, and that each of those words is to be so interpreted in construing the foregoing description and/or the following claims.