AU2016205002C1 - Methods and compositions for administration of iron - Google Patents

Abstract

The present invention generally relates to treatment of iron-related conditions with iron carbohydrate complexes. One aspect ofthe invention is a method of treatment ofiron related conditions with asingle unit dosage of at least about 0,6 grams of elemental iron via an iron carbohydrate complex. The method generally employs iron carbohydrate complexes with nearly neutral pH, physiological osmolarity, and stable and non immunogenic carbohydrate components so as to rapidly administer high single unit doses of iron intravenously to patients in need thereof

Description

AUSTR IA

PATENTSACT 1990

REGULATION 32

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, Melboune, Southbank, Victoria,3006.

Invention Title

"METHODS AND COMPOSITIONS FOR ADMINISTRATION OF IRON"

DetailsofAssociated Provisional Applications Nos

The followingstatement is a full description ofthis invention including the best method of performing it knowinto us

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CROSS-EFRENE PTO RELATED APPLICATIONS

01 This applicationis a division apphcaon derivedfrom Australan Patent Appication No.2013206429whih is turnis a'davstonalapplcaonodriedrom Australian ParentApplcation No.2007205167(P011132007/00076O 207/081?44)claiming priority ofUSApplhcaion No 6W/7571f9 and 1/620986 thentiretext ofwhich are hereby incorporated herein by rferene 10 00 2) The present invention generally relates to treatment ofion ated conditions witiron carbohydratecomplexesi

BACKGROUND

o00031 Parenteral iron therapy Is known to be effective in avarietyofdiseasesand 10 conditions including, but not limited tosevere iron deficiency, front deicincy anemiaproblems ofintestnalronabsorptionIntestinalironintolerance, caseswheereguarIntakeofanoraliron preparations not guaranteed Iron deficiency where tiere is noresponse to oral therapy(g dialysis patients), and situations where iron stores are scarcelyor not at all formed but would be important for furthertherapy (e.w in combination with erythropoetin) Geisser etat. I5 Arzneintteforschung(199242(2)14391452, Thereexistvariouscommerciallyavailable parenteral Iron forwmuations But many currently availableparenteralIron drugswhile purportedly effective at repleing Iron stores have health riskand dosagelimitations associated with their use.

[00041 Currently available parenteral ironformutaons approved for pse In the U$ 21 include iron dextran(eInFedDexforrum), sodium ferric gluconate complex in sucrose (FenleciQ, and iron sucrose (Venofe).AIhoughserious andlife-threateninag racdons occur most frequently with Iron dextran, they are also known to occur with other parenteal Ion produts. Inadditionnon-life threatening reactions such as arthralgia, back pain, hypotension, fever, myalgiapruritus,vertigoand vomiting aso occur. These reactions, while notlife threatening, often preclude further dosing and therefore iron repletion (0oos) Iron dextran, the firstparenteraliron product available in the United States (US) has been associated with an ncidence of anaphylactoid-typereactionedyspnea, wheezing chest pain, hypotension, urticariangioedema) See generaflyFishbane,Am J Kidney Dis (2003)41(5Suppl) 1826; Landryot at (2005) Am J Nephrol 25. 400-410,407 This high incidence of anaphytactoid reactions is believed to be caused by the formation of antibodies to the dextran moiety. Other parenterairon products (e iron sucrose and irongluconate) do not contain the dextran moietyand the incidence ofanaphylaxis with these products is markedly lower. FishbaneAm J Kidney Dis (200)41(SSuppl),8-26;Gesser eta, Arzneimitteforsciung(1992) 42(12),1439-52. However, the physical characteristics of, for

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-I A, exampleIron gluconate and iron sucrose lead to dosageand administration ratelimitations. Negative characteristics include highpH high osmolartylow 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 ' 3.5 hours as a dripinfusion). Furthermore, injectable high molecular mass substances produce more allergic reactions than the corresponding low molecular mass substances, Geisser et at (1992) Arzneimiftelforschung 42:1439-1452 LOO61 Ferumoxytol is a newer parenteraliron formulation but limitedInformation Is available as to itsefficacy and administration See e.g. Landry et a.(2005) Am Nephro 25, to 400-410,408;and Spinowitz et al (2005) Kidney Intl 68,1801-1807;US. Patent No.6,599,498, (0 0071 Various pharmacokinetic studies suggest that doses ofiron 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 al, (1992) Arzneimittelforschun 421439-1452. For exampleto achieve Iron repletionunder current therapy models, a total dose of 1 g typically requires 5 to 10 sessions over anextended period of time. These delivery modes Incur significant expense for supplies such as tubing and infusate costlynursing time, multiple administrations, and patient inconvenience SUMMARY OF THE INVENTION fooosj Among the various aspects ofthe present invention is the provision of a method of treatment of iron-associated diseasesdisorders, orconditionswith iron formuations, Briefly, therefore the present invention directed to use of iron carbohydrate complexes that can be administered parenterally atrelatively high single unit dosages, thereby providing a safe and efficient means for deivery of a total dose of iron in fewer sessions over the course of therapeutic treatment 23 (00091 The present teachings include methods of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism through the administration of at least 0.6grams of elemental iron via a single unit dosage of an iron carbohydrate complex to a subject that is in need of such therapy. t00o) In various embodiments, the method treats anemia. In some embodiments, 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 chronic ingestion of alcohol, chronic ingestion of saicylates, chronic ingestion of steroids; chronic ingestion of non-steroidial anti-inflammatory agents, or chronic ingestion oferythropolesis stimulating agents. in some aspects, the anemia is anemia of chronic disease, such as rheumatoid arthritis cancer;Hodgkinsleukemi; non-Hodgkins leukemia; cancer chemotherapy; inflammatory bowel disease; ulcerative olitis thyroiditis;hepatitis; systemiclupuserythematosus polymyalgia rheumatica; scleroderma; mixed connective tissue disease; Soigrens syndrome congestive heart failure Icardiomyopathy; or idiopathic geriatric anemia. In some embodiments, the anemia is due to impairedIron absorption or poor nutritionsuch as anemia associatedwith Crohn's Disease; gastric surgery;ingestion of drug products that inhibit iron absorption; and chronic use of calciur In various embodiments, the method treatsrestess leg syndrome;blood donation; Parkinson's disease; hair loss; or attention deficitdisorder

[0011) in various embodiments, thesingle dosage unit of elemental iron is between at least about 0.6-grams and 2.5 grams. in someembodimentsthe singe dosage unit of elemental Iron is at least about 0.7 grams; at least about 08 grams; at least about09 grams at least about 1.0 grams; ateast about 11 grams; at least about 1.grams;at least about 13 grams; at least about 1 gramsm; at least about 1.5 grams; at least about 16 grams; at least about 1 grams; at least about1.8 grams; at least about 1.9 grams; at least about 2.0 grams; at least about 2 grams: at least about 2:2 grams: at least about 2.3grams; atleast about2.4 grams; or at least about 2.5 grams. (0012 In various embodiments, the single dosage unit of elemental iron is administered in about 15 minutes or less. In some embodimentsthe single dosage unitof elementalfron Is administeredin about.10 minutes or less,about 5 minutes or less, or about 2 minutes oress, 100131 invarious embodiments, the subject does not experience a significant adverse reaction to the single dosage unit administration,

[0014] In various embodiments, the iron carbohydrate complex has apH between about5.0 to about 7: physiological osmolarity;an iron core size opgreaterthan about 9 nm; a mean diameter particle size no greater than about 35 nm; a bod half4ife of between about 10 hours to about 20 hours; a substantially non-immunogenic carbohydrate component; and substantially no cross reactivitywith anti-dextran antibodies

0 015] n various embodiments, the iron carbohydrate complex contains about 24%to about32% elemental iron; contains about 25% to about 50% carbohydrate; has a molecular weight of about 90,000 daltons to about 800,000 daltonsor some combination thereof. In various embodiments, the iron carbohydrate complex is an iron monosaccharide complex,aniron disaccharide complex, oran iron polysaccharide complex. In some embodiments, the iron carbohydrate complex isiron carboxymalose complexiron mannitol 3$ complex, iron polyisomaltose complex, iron polymaitose complex, iron gluconate complexiron 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 embodimentsthe 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 350,00 daltons, In some preferred embodiments, theIron carboxymaltose complex is obtained from an aqueous solution of iron lil) saltand an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochorite solution at apHvalue within the alkaline range, wherein, when one matodextrin isapplied, its dextrose equivalent lies between 5 and 20, and when a mixture of several matodextrins is applied, the dextrose equivalent lies between 5 and 20 and the dextrose equivalent of eachIndividual matodextrin contained in the mixture lies between 2and 20. In some preferred embodimentsthe iron carboxymaitose complex has a chemical formula of [FeO(OH AH) HOO5) (CH1207)) ,where n is about 103,m is about S, I is about 11, andk Is about 4;contains about 28% elemental ironand has a molecular weight of about 150,000 Da In some preferred embodiments, the iron carboxymatose complex is polynucear iron ()-hydroxide 4(RMpoly---4)O-aolucopyranosyl)-oxy-2(R)3(S),5(R), tetrahydroxy-hexanoate. tn I0 16 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 embodimentsthe 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.

(00171 in various embodiments, the mean size of a particle of the iron carbohydrate complex is no greater than about 35 rmIn some embodiments, the particle mean size is no greater than about 30 nrm In some embodiments, the particle mean size is no greater than about25nm. In some embodiments, the particle mean size isno greater than about 20 nm; no greater than about 15 nm; no greater than about 10 nm; or at least about 6 nm but no greater than about 7 nm. toou18 In various embodiments, the iron carbohydrate complex is administered parenterally, for example intravenouslyorintramusculary. In some embodiments, the iron carbohydrate complex Is intravenously Infused, in certain embodiments, the single unit dose of iron carbohydrate complex isintravenously 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 ofdiuent or about215mlofdiluent. in some embodiments, theIron carbohydrate complex f5 intravenously injected as a bolus In certain embodiments, the iron carbohydrate complex la intravenously injected as a bolus at a concentration of about 1000mg elemental iron inabout 200mItoabout 300 ml of diluent, for example, about250 ml of diluent or about 215 ml of diluent In some embodiments, the iron carbohydrate complex is intramuscularly infused at a concentration of about 1000 mg elemental iron in about 200 ml to about 300 ml of diluent, for example, about.250 ml of diluent or about 215 mi of diluent. In some embodiments, the iron carbohydrate complex is

Intramuscularly infused at a concentration of about 500 mg elemental iron in less than about 10 mi diluent.

tooi;9 In various embodiments, the method also includes a second administration of the iron carbohydrate complex upon recurrence of at least one symptom of the treated disease disorder, or condition. (0020] In various embodiments, the method also includes a second administration of the iron carbohydrate complex after Iday to 12 months after the first administration. (o0211 Ina preferred embodimentthe methodof treating a disease, disorderor condition characterized by Iron deficiency or dysfunctionaliron metabolism comprises 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.ml to about 300 ml of diluent in about 5 minutes or less; wherein theiron carboxymatose compex comprises an iron core with a mean Iron core size of at least about Inm butnogreater than about 9 nm*mean size of a particle of the iron carboxymaltose complex Is nogreater than about35 nm; and the iron carboxymaltose complex is administered intravenously infused or intravenously injected at a concentration of about 1000 mg elemental iron In about 200 ml to about 300 ml of dilueant In some these embodiments, theiron carboxymaltose complex is polynuclear iron (I)-hydfoxide 4(R>{poly-(1-4-O--glucopyanosyt)-oxy 2(R),3(S)5(R),6-tetrahydrotyhexanate. In some these embodiments, the iron carboxyrnaltose complex is obtained from an aqueous solution of Iron (I) salt and an aqueous solution of the oxidation productof one or more maltodextrins using an aqueous hypochlorite solution at a pH value within the alkaline rangewherein, when one maltodextrin is applied, its dextrose equivalent lies betweenabout5 and about 20, and when a mixture of several maitodextris is applied,the dextrose equivalent lies between about 5 and about 20 and the dextrose equivalent of each individual matodextrin contained in the mixture lies between about 2 and about 20. t0022) Otherobjects and features will be in part apparent and impart pointed out hereinafter,

BRIEF DESCRIPTION OF THE DRAWINGS

[0023) Those of ski lIn the art will understand that the drawings, described below, are for illustrative purposes only The drawings are not intended to limit the scope of the present teachings In any way. 10024) FIG I 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 Dexforrum (an iron dextran). FIG I Bis an electron micrograph depicting the particle size of Venofer (an iron sucrose). FIG I Cis an electron micrograph depicting the particle size of polynuclear iron (I)-hydroxide 4(R)-(poly-(I-*4)-O-d-glucopyranosyl)-oxy.2(R)5 3(sx5(R)o~ tetrahydroxy-hexanoate (VT-45,an ron carboxymaltose complex).

[00251 FIG 2 is a schematic representation ofan exemplaryIron carboxymtalose complex. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention makes use of iron carbohydrate complexes that can be administered parenterally at relatively high single unit dosages for the therapeutic treatment of a variety of iron-associated diseases, disorders, or conditions. Generally, states indicative of a need for therapy with high single unit dosages ofironcarbohydrate complexes includebut are tO not limited to iron deficiency anemlaanemia of chronic disease, and states characterized by dysfunctional iron metabolism Efficacious treatment of these,and other, diseases andconditions with parenteraliron formulations (supplied at lower single unit dosage than those described herein) Is generally known in the art. See e.g. Van Wyck et al (2004)J AM So Nephro15, 391-S92 The present invention Is directed to use ofIroncarbohydrate complexes that can be administered parenterally at relatively high single unit dosages, thereby providing a safe and efficient means for delivery of a total dose of iron infewersessions over the course of therapeutic treatment.

[002-7 Iron deficiency anemia is associated with,for example, chronic blood loss acute blood loss; pregnancychildbirth; childhood development; psychomotor and cognitive development in children; breath holding spells; heavy uterinebleeding menstruation; chronic recurrent hemoptysis; idiopathic pulmonary siderosis; chronic1nteral bleeding; gastrointestinal bleeding; parasitic infections; chronic kidney disease; dialysis; surgery or acute trauma; and chronicingestion of alcohol chronic ingestion of salicylates, chronic ingestion of steroids; chronic ingeston of non-steroidial anti-inflammatory agents, or chronic ingestion of erythropoiesis stimulating agents.

£002Bn Anemia of chronic disease is associated with, for example, rheumatoid arthritis; cancer Hodgkins leukemia;non-Hodgkins leukemia; cancer chemotherapy; inflammatory bowel disease; ulcerative colitis thyroidiis; hepatitis; systemic lupus erythematosus; polymyalgia rheumatica; sceroderma; mixed connective tissue disease; Sojgren's syndrome; congestive heart failure I cardiomyopathy; and idiopathic geriatric anemia.

[0029) Anemia is also associated with, for exampleCroh's Disease; gastric surgery; ingestion of drug products that inhibitIron absorption; and chronic use ofcalcium.

£0030 States characterized by dysfunctional iron metabolism and treatable with the single unit dosages of Iron carbohydrate complexes described heroin include, but are notlimited to, restless leg syndrome; blood donation; Parkinson's disease; hair loss; and attention deficit disorder

(0031] Again,each of the above listedstates, diseases disorders, and conditions, as well as others, can benefit from the treatment methodologies 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, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can alsoInclude Inhibiting the state, disease, disorderor 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, diseasedisorder or condition or at least one of its clinical or subclinical symptoms.

[0032) 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 normailevels. Thus,efficacy ofIron replacement therapy can be interpreted in terms of the ability to normalise Hb 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 inanemic patientsIron stores can be assessed by interpreting serum ferritin levelsTfS is frequently used, inaddition, to diagnose absolute or functional irondeficiencies.In patients with Iron deficiency, serum transferrin Is elevated and will decrease following successful Iron treatment. (0033) Administration (0034) Methods of treatment of various diseases, disorders. or conditions with iron complex compositions comprise the administration of theomplex in single unit dosages of at least 0.6 grams of elemental iron toaboutatleast 25 grams of elemental iron Administration of single unit dosages can be, for example, over pre-determined time intervals o riresponse to the appearance and/or reappearance of symptoms For examplethe iron carbohydrate complex can be re-administered upon recurrence of at least one symptom of the disease or disorder.As another example, the iron arbohydratecomplex can bere-administered at some time period after the Initial administration (e.g., after 4 days to 12 months)

[00,35J 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 administeredparenterally, for example Intravenously or Intramuscularly, Intravenous administration can be deliveredas a bolus or preferably as an infusion. For example, the single unit dose ofironcarbohydrate 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 ml of diluent or about 260 ml of diluent. The iron carbohydrate complex can be intravenously injected a a bolus. For example, theiron carbohydrate complex can be intravenously injected as a bolus at a concentration of about1000 mg elemental iron in about 200 mi to about 300 mI of diluent, preferably about 215 ml of diluent or about 250 mi of diluent' TheIron carbohydrate complex can be intramuscularly Infused at a concentration f for example, about 1000 mg elemental iron In about 200 in to about 300 ml of diluent, preferablyabout 250 ml of diluent orabout 215 nil of diluent Ifapplied as aninfusion the iron carbohydrate complex can be dilutedwith sterilesaline (e.g., polynuclear iron () hydroxide 4(R)-(poly-(4--.4)-OCaoglucopyranosy)-oxy-2(R)3(S),5(R)6-tetrahydroxy-hexanoate ("VIT-45") 0.9%aN NaClor 500 mg iron i up to 250 rL Na). The iron carbohydrate complex can be intravenously injected as abolus 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 mi diluentpreferably about 5 ml.

[o361] Generally,totaliron dosage willdepend on the iron deficitof the patient. One skilled in the art can tailor the totalIron doserequired for a subject while avoiding iron overload, as overdosing with respect to the total required amount of iron has to be avoided, as is the case for all tron preparations. t00371 The total Iron dosagecan be delivered asasingle unitdosageoraeriesof single unit dosages. An appropriate single unit dosage level wl generally be at least grams of elementalIron, particularly at least 0.7 grams;atleast 0.8 grams; at least 09 grams; at least .0grams; at least 11 grams; at least12 grams;at least 1.3 grams; at least 14 grams; at least 1.5 grams; at least 1 .6 grams; at least 1.7 grams; least 1 grams; at least 1.9 grams; at least 2.0 grams;at least 2. grams; atleast 2.2 grams; at least 2.3 grams; at least 24grams, or at least 2.5 grams. For example, a single unit dosage is at least 1.0 grams of elementaliron As another example, a single unit dosage is at least 1.5 grams of elementalI ron. As a further example,a single unit dosage is at least 2.0grams of elemental iron. In yet another example, a single unit dosage is at least 2.5gramsof elementaliron. too03a An appropriate single unitdosagelevel 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 least10,5 mg/kg, at least 12 mg/kg, at least 135 mg/kg at least 15 mg/kg, at least 16.5 mg/kg, atleast18 mgkg, at least 195 mg/kg, at least 21mg&g, at least 22.5 mggat least 24 mg/kg, at least255 mgkgat least 27mgkg, atleast 285 mgkgat least 30 mgg, at least 31.5 mg/kg. at least 33mg/kg; at least 345 mg/kg, at least 36 mg/kg, or at least 37.5 mg/kg

[00393 Preferably, a single unit dosage can be administered In15 minutes or less. For example,the single unit dosage can be administered in 14 minutes or less, 13 minutes or less,12 minutes or less, IIminutes or less,10 minutes or less, 9 minutes or less, 8 minutes or less,7minutes 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 ironcan occur as aone-time deliveryofa single unit dose or over a-course of treatment involving delivery of multiple single unit doses. Multple single unit doses can be administeredfor example,over pre-determined time intervalsor in response to the appearance and reappearance of symptoms. The frequency of dosing depends on the disease or disorder being treated, the response of eachIndividual 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 canbe, for example, a course of therapy once every day to once every eighteen months,

[00411 Such consecutive single unit dosing can be designed to delivera relatively high total dosage of iron over a relatively low period of time. For example, a single unit dose (e.g. 1000 mg) can be administered every 24 hours. As illustration, a total dose of 2000, 2500, 3000, 3500,4000.4500, or 5000mg of elementairon can be delivered via consecutive daily single unit doses of about 600 mg to about 1000 mg of elemental iron. Given that a singleunit dose of 1000 mg can be intravenously introduced intoa 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 elementalIron.

t00421 As another example, a single unitdose can be administered every 3-4 days. As a further example, asingle unit dose can be administered once perweek. 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 bymedical professionals, t00431 It will be understood, however, that the specific dose and frequency of administration for any particular patient may be varied and depends upon a variety of factors, including the activity of the employed iron complex, the metabolic stabilityand length of action of that complex, the age. body weight, general health, sex, diet, mode andtime ofadministration, rate of excretion, drug combination, the severity and nature of the particular condition, and the host undergoing therapy.

[0044) The folloving provides but a few examples of treatment protocols for various diseases or disorders.

[00451 Iron carbohydrate complexcan be given as a single unit dose for the treatment of Restless Leg Syndrome. For example, 1000 mg of elemental Iron from an iron carboxymaftose (e.g. polynuclear iron (il)-hydroxide4(R(poly-(t- 4)~Oglucopyranosyl)~oxy 2(R),3(S);5(R),&tetrahydroxyhexanoate) canbe intravenously Injected as a single dose (e.g., 1.5-5 mg ironrnW in normal sane) to a subject suffering from Restless Leg Syndrome, A single intravenous treatment can provide relief of symptoms for an extended period of time, approximately two to twelve months, although relief may be granted for shorter or longer periods, See U.S. Patent Pub. No. 20040180849, incorporated herein by reference. Ifdesired,post infusion changes in central nervous system ironstatus can be monitored using measurements of cerebral spinal fluid (CSF) ferrtin (and other iron-related proteins) and of brain Iron stores using MRl 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) measures of clinical status, If desired, to better evaluate RLS symptom amelioration. CSF and serum iron values, MRI measures of brain iron and full clinical evaluations with sleep andimmobilization tests are obtained prior totreatment, approximately two weeks after treatment, and again twelve months later or when symptoms return, Clinicalratings, Leg Activity Meter recordings and serum ferritin are obtained monthly after treatment. CSF ferritin changes can also be used to assess symptom dissipation, LO046) Iron carbohydrate complex can be given as a single unitdose for the treatment of iron deficiency anemia secondary to heavy uterine bleeding For example. a single unit dose 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 Ferritln <50 ng/m Dose = Baseline weight (kg) x (1I5-aseline gb g/dLj) x 2.4 + 500 mg OR If baseline TSAT>20%and BaseincFerritin > 50 ng/mL Dose =Baseline weight (kg) x (15-Baseline Hgb [g/dL]) x 2 (NOTE Baseline Hgb equals the average of the last two centrallab Hgb's) £00471 Iron carbohydrate complexcan be given as a single unit dose for the treatment of iron deficiency anemia A subject diagnosed assufering from Iron deficiency anemia can be, for example, ntravenously injected with a dose of 1,000 mg of Iron asVIT-45 (or 15 mgkg for weight 66 kg)in 250 cc ofnormal saline over 15 minutes. Subjects with iron deficiency anemia secondary to dialysis or non-dialysis dependent-Chronic Kidney Disease (CKD) as per KDOQ guidelines will generally have Hgb <12 g/dL;TSAT < 25%;and Ferritin300 ng/mL. Subjects with iron deficiency anemia secondary to Inflammatory Bowel Disease will generally have Hgb < 12 g/dL: TSAT< 25%; and Ferritn < 300 ng/mL Subjects withiron deficiency anemia secondary to other conditions will generally have Hgb 12 gfd.TSAT < 25%and Ferrifin <100 ng/mL (0048] 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 deliverIron rapidly or in higher doses and/or in subjects with functional iron deficiency such as those on erythropoetin therapy. A determination of the need for treatment with parenteral iran is within the abilities of one skilled in the art. For example, need can be assessed by monitoring a patient's iron status, The diagnosis ofiron deficiency can be based on appropriate laboratory testsfor example, haemoglobin (Hb), serum Sferitin serum irontransferrin saturation (TfS), and hyporomic red cells t0050] A determination of the need for treatment with high dosages of parentera iron can be also be determined through diagnosis of a patient as suffering from a disease, disorder, or condition that is associatedwithIron deficiency or dysfunctional iron metabolism. For examplemany chronic renal failure patients receiving erythropoietinwill requireintravenous ron to maintain target iron levels. As another example, most hemodialysis patients will require repeated intravenous iron administration, due to dialysis-associated blood loss and resulting negative iron balance, F0051 Monitoring frequency can depend upon the disease, disorderor condition the patient is afflictedith or atrisk for, For examplein a patient initiating rythropoiein therapy, iron indices are monitored monthly. As another exampleIn patients who have achieved target range Hb or are receiving intravenous iron therapy, TSAT and ferritin levels can be monitored every 3 months.

(0052J A patient's iron status can be indicative of anabsolute ora functional iron deficiency,both of which can be treated with the compositions and methods described herein. 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 bloavallability of dietary iron,increased utlization of ironor chronic blood loss, Prolonged iron deficiency can lead to iron deficiency anemia-a microcytlic hypochromic anemia in which there are inadequate iron stores. Absolute ron deficiencyis generally indicatedwhere TSAT <20% 2$ and Ferritin <100 ngmL

[00!5) Functionaliron deficiency can occur where there is a failure to release iron rapidly enough to keep pace with thedemands of the bone marrow for erythropoiesis, despite adequate total body iron stores. in these cases, ferritin levels may be normal or highbut the supply of Iron to the erythron is limited, as shown by alow transferrin saturation and an increased number of microcytic, hypochromic eryithrocytes 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, FunctionalIron deficiency (i,iron stores are thought to be adequate but unavailable for iron delivery) is generally indicated where TSAT <20%and Fernitin >100 ng/mL.

(0054J Assessing the need for intravenous iron therapy as described herein can be according to the National Kidney Foundatiori's Kidney Disease Outcomes Quality Initiative. Se&

NKF-K/DOQI,Clinical Practice Guidelines for Anemia of Chronic Kidney Disease (2000);Am J Kidney Dis (2001) 37(supp 1), S182-S238. TheDOQl provides optimal clinical practices for the treatment of anemia In chronic renal failureThe DOQ guidelines specify intravenous iron treatment of kidney disease based on hemoglobin, transferrin saturation (TSAT), and ferritin levels.

[0055) Assessment of need for intravenous iron therapy can also be according toa patient's target iron level. For example, the target hemoglobin levelof a patient can be selected as 110 g/dL to 12g/dL (hematocrit approximately 33% to 36% To achieve targethemoglobin with optimum erythropoletin dosessufficientiron, supplied via an iron carbohydrate complex is provided to maintain TSAT 220% and ferritin 100ng/mLn erythropoeitin-treatedpatentsif TSAT levels are below 20%, thelikelihood that hemoglobin will rise or erythropoietin doses fall after Iron administration is high. Achievement of target hemogobin levels with optimum erythropoietin doses Is associated with providing sufficient iron to maintain TSAT above 20%.

[oos6 Iron therapy can be given to maintain target hemoglobinwhile preventing iron deficiency and also preventing iron overload. Adjusting dosage of iron to maintain target levels of hemoglobin, hematocritand laboratory parameters of iron storage is within the normal skill in the art For example, where a patientis anemic or ron deficient intravenous iron can be administered when a patient has a ferriin <800 a TSAT<50, and/or a Hemoglobin <12. Iron overload can be avoided by withholding iron for TSAT'>50% and/or ferridn >800 ng/mL 10057 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 TSAT levels are not necessarily relevantwhile ferritin >800 can still provides a general cutoff point for administration. (oos1] lron Carbohydrate Complex 0059] Iron carbohydrate complexes are commercially availableor have well known syntheses. Examples of iron carbohydrate complexesIncludeIron monosaccharide complexes, iron disaccharide complexes,iron oligosoccharide complexes, and Iron polysaccharide complexes, such as:iron carboxymatoseiron sucrose, iron polyisomatose (irondextran),iron polymaltose (Iron dextrin), iron gluconate, iron sorbitol,iron hydrogenated dextran, which may be further complexed with other compounds, such as sorbitolcitrc acid and gluconic acid (for example iron dextrin-sorbitolcitric acid complex and Iron sucrose-gluconic acid complex), and mixtures thereof. 100603 Applicants have discovered that certain characteristics ofiron carbohydrate complexes make them amenable to administration at dosages far higher than contemplated by current administration protocols. PreferablyIron carbohydrate compexes for use Inthe methods described herein are those which have one or more of the following characteristic; a nearly neutral pH (eg about 5 to about 7); physiological osmolarity; stable carbohydrate component; an iron core size no greater than about 9nm;mean diameter particle size no greater than about 35 nm, preferably about 25 nm to about 30 nm; slow and competitive delivery of the compexed iron to endogenous iron binding sites; serum ha-ife of over about 7 hours; low toxicity; non immunogenic carbohydrate component; no cross reactivity with antidextran 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. Ukewise, 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;TableI The stability of the carbohydrate complex can be assessed through physicochemical properties such as kinetic characteristics thermodynamic characteristics, and degradation kinetics. See Geisseretal Arznelmittelforschung (1992)42(12),1439-1452. Useful techniques to assess physical and electronic properties include absorption spectroscopy X-ray diffraction analysistransmission electronmicroscopyatomic force microscopy, and elemental analysis. See Kudasheva et al (2004) Jtnorg Biochem 98,17571769 Pharmacdkinetics can be assessed, for example, by iron tracer experiments. Hypersensitivity reactions can be monitored andassessed as described in, for example, Bailie et al.(2005) Nephrol Dial Transplant, 20(7),1443-1449 Safety, efficacy, and toxicity inhuman subjects can be assessed, for example, as describedInSpinowitz et at. (2005) KidneyIntl68, 1801-1807, (00621 A particularly preferred iron carbohydrate complex will have a pH between 50 0; physiological osmolarity;an iron core size no greater than 9 nm; mean diameter particle size no greater than 30 nm;serum half-ife ofover 10 hours; a non-immunogenic carbohydrate component and no cross reactivity with anti-dextranantibodies One example of a preferred iron carbohydrate complex for use in the methods described herein is an iron carboxy-matose complex (e.g. polynuclearIron ii)-hydroxide 4(R4poy-(-4)~-O-o-glucopyranosy)-Oxy 2(R),3(S),5(R),0-tetrahydroxy-hexanoate"VIT-45") Anotherexample ofa preferred iron carbohydrate complex for use in the methods described herein is acarboxyakylated reduced polysaccharide iron oxide complex (e.g. ferumoxytol, described in US. Patent No 6,599,498), (0063] 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 Inmethods 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 datons to about 800,000 datons more preferably 100,000 daltons to about 350,000 daltons, to064) Iron carboxymaltose complex

(00ss1 One preferred Iron carbohydrate complex for use inthe methods described herein is an iron carboxymatose complex. An example of an iron carboxymaltose omplex is polynuclear iron (l)-hydroxide 4(R-poy(14)O-a-gucopyranosy) oxya2(R)(S)(R6 tetrahydroxy-hexanoate ("VIT45") VIT-45 is a TypeI polynuclear iron (111) hydroxide carbohydrate complex that can be administered as parenteral iron replacement therapy for the treatmentofvarious anemip-related conditions aswell as otheriron-metabolism related conditions. VIT-45 can be represented by the chemical formula; JFex(OH)y(H20)zn j((C61005)m (C6H1207)}l)k, where n is about103,m is about 8, 1is about Iand k is about 4). The molecular weight of VIT-45 is about 150,000 Da. An exemplary depicton ofVIT-45 is provided in Figure 2.

[00661 The degradation rate and physicochemicalcharacteristics of the iron carbohydrate complex (eg, VIT-45) make it anefficient means of parenteral iron delivery to the body stores, itis more efficient andless toxic thanthetowermolecular weight complexes such as iron sorbitolcitrate complexand does not have the same limitations of high pH and osmolarity that leads to dosage and administration rate limitations in the case of, for example, iron sucrose and iron gluconate

[00671 The iron carboxymaltose complex (e.g., VIT-45) generally does not contain dextran and does not react with dexran antibodies; therefore, the risk of anaphylactod /hypersensitivity reactions is very low compared to iron dextran. The ironcarboxymaltose complex (egqVIT-45) has a nearly neutral pH (5,0 to 70) and physiologicalosmolarity which makes it possible to administer higher single unit doses over shortertime periods than other iron carbohydrate complexes. The iron carboxymaltose complex (ag. VIT45) can mimic physioogicaly occurring ferritin. The carbohydrate molety of iron carboxymatose complex (e.g. VT-45)i metabolized by the glycolytic pathway. Like iron dextran, theiron carboxymaltose comrnplex (eg-VIT-45) is more stable than iron gluconate and sucrose. The- ion carboxymaltose complex (e.g.ViTA-5) 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, Higher single unit doses can result in the need for fewer injections to replete iron storesand consequently is often better suited for outpatient use.

[0068) After intravenous administration, the iron carboxynaltose 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 initialelimination of radioactively labeled iron (Fe) 2 Fe"Fe ViT-45 from the blood, withrapid transfer tothe bone marrow and rapid depositon in the liver and spleen. See eg, Bshara et at (2003) Br J Haematol 2003; 120(5): 853859. Eight hours after administration to 20% of the injected amount was observed to be stillIn the blood, comparedwith 2 to 13% for Iron sucrose. The projected calculated terminal half-life (tA) was approximately 16 hours, compared to 3 to 4days for iron dextran and 6 hours for iron sucrose. (00691 The iron in the iron carboxyialtose complex (e.gViT-45) slowly dissociates 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 ofiron carboxymaltose complex occurs inanemic patients, In addition, the reticuloendothelial uptake of this complex reflects the safety of

, polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of alargeinterstitial transport pool (e.g, transferrin)

[0070) Other studies inpatients 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 these studies, VIT-45 demonstrated a monoexponential elimination patterwith a t1 , in the range 7 to 18 hours,with negligible renal elimination.

[00711 Singe-dose toxicitystudies have demonstrated safety and tolerance in rodents and dogs ofIntravenous doses of an iron carboxymatose complex (VIT-45) up to 60 times more than the equivalent of an intravenous infusion of 1,000 mg iron once weeklyin humans. Pre-clinical studies In dogs and ratsadministered VIT-45 in cumulative doses up to 117 mg iron/kg body weight over 13 weeks showed no observed adverse effectlevel 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 intravenoustolerancestudies in the rabbit In vitro and invivo mutagenicity tests provided no evidence that VIT-45 is clastogenic. mutagenic, or causes chromosomal damage or bone marrow cell toxicity, There wereno specific responses to VIT-45 in a dextran antigenicity test.

[0 0721 Approximately 1700 subjects have been treated with an iron carboxymatose complex (VIT45) 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 VT-45 over 15 minutes intravenously. Few adverse events and no serious adverse events orwithdrawals due to adverse events related to VIT45 administration have been reported. No clinically relevant adverse changes in safety laboratories have been seen,

[00731 The physicochemical characteristics of the iron carboxymaltosecomplex(e. VIT-45), the pattern of iron deposition, and the results of the above described studies demonstrate that iron carboxymaltose complex can be safely administered at high single unit therapeutic doses as described herein.

£0074] Polyglucosesorbitolcarboxymethylether-coatednon-stoichometricmagnetite £0075) Anotherpreferred Iron carbohydrate complex for use in the methods described herein is a polyglucose sorbito carboxymethy ether-coated non-stoichiometric magnetite (eg., ?ferumoxytor). Ferumoryto is known n the art to be effective fortreating anemia (atsingle unit doses lower than described herein). ee e.g., Spinowitzat a (2005) KidneyIntl 681801-1807 Ferumoxytol Isa 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 U.S Patent Noa6,599,498,incorporated herein by reference Safety, efficacy and pharmacokinetics of ferumoxytol are as described,for example, in Landry et at (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.

[007r63 The Iron oxide of ferumoxytol is asuperparamagnetic form of non stoichiometric magnetite wth a crystalsize of 6.2 to 7.3 nm. Average coloidal particle size can be about 30 nm, as determined by fight scattering, Molecular weight is approximately 750 kD, The osmolarity of ferumoxytol is sotonic at 297 msm/kg and the pH is neutral. The blood half life of ferumoxytol is approximately 10-14 hours. It has been previously reported that ferumoxyto can be given by direct Intravenous push over 1-5 minutes in doses up to 1,800mg elemental iron per minute, with maximal total dose up to 420 mg per injection. Landry et al, (2005) Am J Nephrol25, 400410, 408

[00773 CoreandParticleSize (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 ofcarbohydrate that stabilizes the ron-oxyhydroxide, slows the release of bioactive iron, and maintains the resulting particles in coloidal suspension. Iron agents generallyshare the same core chemistry but differ from each other by the size of the core and the identity and the density of the surrounding carbohydrate, See Table 1; FIgure1

Table 1: Core and Particle Size of Iron Carbohydrate Complexes

Iron (Ill) Control Release Test Size of the Particle (nm) +- SEM

T7 5 (min) fIron core Total Particle

Dexferrum (an iron dextran) 122.5 11,8; ±4 27 6

VIT -45 (an iron carboxymaltose) 117.8 4.4 ±i.4 6,7 2,5

Venofer (an Iron sucrose) 10,2 2.8 ± 1 65 ± 4

[00791 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 bloactivity in vivo, and maximum tolerated dose and rate of infusion,

[00801 One of the primary determinants ofiron bloactivity is the size of the core and the surface area to volume ratio. Generally, the rate of labile iron releasein each agent is inversely related to the size of itsiron core. Van Wyck (2004) J. Am. Soc, Nephrology 15, S107 $111,$109. Furthermore, in vitro iron donation totransferrin is inversely related to core size. Core size can depend upon the numberof iron atoms containedwithin. Forexample, the number of iron atoms contained within a I nm core is calculated to be 13, while a 10 nm corels calculated to contain 12770 iron atoms. Where agents share thesamecorechemistry,therate of iron release per unit surface areais 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 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 foriron 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,

[005.11 A smaller Iron coresize of anIron complex administered for the treatment of various diseases, disorders, or conditions aows wider distribution through tissues, a greater rate of labile iron release, and increasedin vitro iron donation to transforrin. Furthermore. the iron complex is more evenly distributed and metaboizes faster due to the smaller core size. But ifthe core size is too small, the iron complex can moveinto cells unable to metabolize iron. in one embodiment, an iron complex witha 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 nim, about 2 nm, about 3 nm, about 4 m, about r nm, about 6 nmabout 7 nn or about nm. Mean iron core size can beforexample, between about inm and about 9 nrm; between about 3 nm and about 7 nm or between about 4 nm and about 5 nm E0023 The molecular weight(he, 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 (ke, biological available) Iron is inversely correlated with the molecular weight of the iron-carbohydrate complex. Van Wyck (2004) J. Am. Soc. Nephrology 15,S107- 11, 8109 That is to say, the magnitude of labilei ron effect Is greatest in iron-carbohydrate compounds of lowest molecular weight and least in those of the highestmolecularweight. Generally, there is a direct relationship between the molecular weight of the agent and the mean diameter of the entire particle (eL the iron core alongwith the carbohydrate shell) in various embodiments,the mean diameter size ofa particle of the Iron carbohydrate compex isnogreater than about 35 nm. For example, the particle mean size can be no greater than about 30 nm. As another example the particle mean size can be no greater than about 25 nm. As another example, the particle mean size can be no greater than about 20 nm. As another examplethe particle mean size can be no greater than about15 nm As a further examplethe particle mean size can be no greater than about 10 nm. As another example, the particle mean size can be no greater than about 7 nm (00833 Absenceof SignificantAdverse Reaction to the Single Dosage Unit Administration (00843 Generally, a safe and effective amount ofan 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, 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 wil occur in less than about 5% of treated patients. For example, treatment-emergent adverse events will occur I less than 4% or 3% of treated patients. Preferably, treatment-emergent adverse events will occur in less than about 2% of treated patients

[oOSJ For exampleminimized undesirabletside effects canInclude those related to hypersensitivity reactionssometimes classified as sudden onset closely related to the time of dosing including hypotensionibronchospasm, layngospasm, angloedema or uticaria or several of these together. Hypersensitivity reactions are reported with all current intravenousiron products independent of dose, See generally Bae t at (2005) Nephrol DialTransplant, 20(7), 1443-1449. As another example, minimized undesirable side effects can include those related to labileiron 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 givenfst s00861 PharmaceuticalFonulations

[00871 In many cases,a single unit dose ofron carbohydrate complex maybe delivered as a simple composition comprising theIron complex and the buffer in which is dissolved.- oweverother products may be addedifdesired, for exampleto maximizeiron delivery, preservation,or to optimize a particular method of delivery.

[008aj A "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatingsantibacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceuticaladministration (see eg.,Banker, Modem Pharmaceutics, Drugs and the PharmaceuticalSciences,4thed(2002) ISBN0824706749; Remington The Science and Practice of Pharmacy, 21sted (2005) ISBN 0781746736) Preferred examples of such carriers or diluents include but are notlimited to, water, saline Finger's solutions and dextrose solution. Supplementary active compounds can also be Incorporated into the compositions. For intravenousadministration,the iron carbohydrmte complex is preferably diluted in normal saline to approximately 2-5 mg/mI. The volume of the pharmaceutical solution is based on the safe volume for the individual patient, as determined by a medical professional,

[00891 An iron complex compositionof the invention for administration is formulated 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, propyene glycol or other syntheticsolvents, antibacterialagents such as benzy alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisuffite; buffers such as acetatescitrates or phosphatesand agents fortheadjustment 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.

[00901 Pharmaceutical compositions suitable for injectioninclde sterile aqueous solutions or dispersions for the extemporaneous preparation of sterle injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostaticwater, Cremophor E(BASF; Parsippany, N.J)or phosphate buffered saline (PBS). The composition must be sterile and should be fluid so as to be administered using a syringe. Such compositions should be stable during manufacture and storage and must be preserved against contamination from microorganisms,such as bacteria and fungi, The carrier can be a dispersion medium containing, for exampe water, polyo(such as glycerolpropylene glycol,and liquid polyethylene glycol),and other compatible,suitable mixtures. Various antibacterial and anti-fungal agents, for example, parabens, chlorbutanol, phenol, ascorbic acid, and thimerosal,can contain microorganism contamination, Isotonic agents such as sugars, polyalcohos, 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 gelatin.

foo91i Sterile injectable solutions can beprepared by incorporating anIron complex in the required amount in an appropriate solventwith a single or combination ofingredients as requiredfollowed by sterilization. Methods of preparation of sterile solids for the preparationof sterile injectable solutions include vacuum drying and freeze-drying to yield a solid containing the iron complex and any other desired ingredient

[00921 Active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems iodegradable or biocompatible polymers can be used, such as ethylene vinyl acetateoyanhydrides, polyglycolic acid,collagen, polyorthoesters, and polylactic 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.

[00933 A single unit dose of iron carbohydrate complex maybe ntravenously administered in a volume of pharmaceutically acceptable carrier of, for example, about 1000 mg of elemental Iron in about 200 mlto about 300 mliof diluent For example, a single unit dose of iron carbohydrate complex may be intravenously administeredin a volume of pharmnaceuticay acceptable carderof about 1000 mg of elemental iron In about 250 ml of diluent As another example, a single unit dose of ron carbohydrate complex may be intravenously administered in a volume of pharmaceutically acceptable carrier of about1000 mg of elementaliron In about 215 ml of diluent.

[00943 A preferred pharmaceutical composition for use in the methods described herein contains VIT45 as the acWe pharmaceutical ingredient(API) with about 28% weight to weight (m/m) of iron, equivalent to about 53% m/r iron (l)-hydroxide, about 37% m/m of ligand, S6% m/m of NaCI, and ;10% /rn of water, (0095) Kits for pharmaceutical compositions

[0096) Iron complex compositions can be included in a kit, container, pack or dispensertogether 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 containerssuch as ampules or vials, and admixed immediately before use, Such packaging of the components separately may permitlong-term storage withoutlosing the activity of the components. Kits may alsoInclude reagents in separate containers that facilitate the execution of a specific test, such as diagnostic tests.

[00971 The reagents included in kits can be supplied incontainers of any sort such that the life of the different components are preserved and are not adsorbed or altered by the materialsof the container, For example,seated glass ampules or vials may containlyophilized iron complex or buffer that have been packaged under a neutranon-reacting gas, such as nitrogen. Ampules may consist of any suitable material, suchas glassorganic polymers, such as polycarbonate, polystyrene, etc., ceramic, metalor any other material typically employed to hold reagents. Other examples of suitable containersinclude bottles that are fabricated from similar substances as ampulesand envlopes that consist offoil-lined interiors, such as aluminumoranalloy. Other containers include test tubes,vials, flasksbottles, syringes,,etc. Containers may have a sterile access portsuch 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 thatupon removal, permits the components to mix. 1$ Removable membranes may be glass, plastic, rubber, etc. 001983 Kits may also be supplied with instructional materials. Instructions may be printed on paper or other substrateand/or may be supplied on an electroni-readable medium, such as a floppy disc, CD-ROM, DVD-ROMmiri-disc SACODZip disc, videotape, audio tape. etc Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an intemet web site specified by the manufacturer or distributor of the kit,or supplied as electronic mail. (009,9 Having descdhed the invention in detail it willbe apparent that modifications, variations, and equivalentembodiments are possible without departing the scope of the invention defined In the appended claims. It should be understood that allreferences cited are Incorporated herein by reference. Furthermoreit should be appreciated that all examples in the present disclosure are provided as non-limiting examples, EXAMPLES

[01001 The following noniaiingexamples are provided to further Illustrate the present invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches the inventors have found function well in the practice of the inventionand thus can be considered to constitute examples ofmodes for itspractice.However, those of skill in the art shouldinlight of the present disclosure, appreciate that many changes can be made in the specflk embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit and scope of the invention

Example 1Non-Toxicty Studies

(0101 Nonclinical toxicity of VIT-45 is very low, as is normal for Type I plynucear Iron (Ill)-h'ydr-oxide c-arbohydrate complexes, The single dose toxicity Is so low that the Lo", could not be estimated and is higher than 2000 mg frono b.w. Mice tested with a singe dose of 1250 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 bw. 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. Example 2: Pharmoldnetic Studies

[0102] Pharmacokineti and red blood cell measurements of rFePFe labelled VIT 45 following v. administration using PET In 6 patients showed a red blood cell utilization from 61 to 9%. The 3 patients withIron deficiency anemia showed a utilization of radolabelled iron of 91 to 99% after 24 days, compared to 61 to 84% for 3 patients with renal anaemia. The terminal ti for VIT-45was calculated to be approximately 16 hours, compared to about 6 hours forIron sucrose. In two further studies in patients with iron deficiency anemia, pharmacokindtic analyses revealed increases in exposure roughly proportional with VIT-4 dose (Cmax approximately 150 pg/mL and 320 pg/mL following 500 mg and 1000 mg doses, respectively), VIT-45demonstrated a monoexponental elimination patten with a tin the range 7 to 18 hours. There was negligible 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 inall studies (where measured), following both single doses and repeated doses. The increase in serum ferritin levels , 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 VT-45 infusion,

(0104) Efficacy of iron replacement therapy is interpreted mainly in terms of the ability to normaise Hblevels and Iron stores. In the multiple dose studies, patients demonstrated a slowly-developing,sustained increase in Hb levels during study participation. in one study, 37% and 48% of patients In Cohorts 1 and 2, respectively, had achieved normal Hblevels at the 4 week follow-up visit, and 75% and 73%, respectively, had achieved a 20 g/L increase in Hb on at least I occasion.

[0105) In another study (patients receiving regular haemodialysis), the majority of patients (61.7%) achieved an increase of Hb of 10 g/L at any point during the study. Serum ferritin and TfS levels showed a more prolonged elevation following repeated VT-45 infusions, indicating a sustained replenishment of iron stores. However elevated levels of ferritin and TfS indicatingiron overload were avoided. In bothof these studies,there was a gradual decrease in transferin over time,also indicating successfuliron replacement.

Example 4:Safety Assessments

[01061 Safety assessments were made in 73 patients with iron deficiency anemia (27 single-dose,46 repeated-dose),and 166 patients with renal anaemia (3 single-dose, 163 repeated-dose) who received VIT-45 at individualron doses of 100 mg up to 1000 mg (cumulative doses of 100 to 2200 mgThese studies showed a safety profile equal to, or exceeding, currently available parentera iron formulations. 10107} 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 signs12lead ECGs or laboratory safety tests.

[0108) in the repeated-dose studies, there were nodeaths attributed toVIT45while 10 patients experienced serious adverse events. Allof these cases occurred in patientswith renal anaemia receiving haemodialysis and were considered not related to the VfT-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 laboratory safety parameters, although there was a low incidence total6 patients) oflaboratory values reported as treatment-related treatment-emergent adverse events (elevated CRP, AST, ALT and GGT, abnormal liverfunction tests and elevated WBC).

[01091 Although many patients inthese2 studies had serun ferritin above 600 pg/L on at leastI occasion during the study, very few patients also had TfS values >50%. Generally, 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

[0,101 The following example demonstrates the safety and effectiveness of parentera VIT-45 in the treatment of anemia In a variety of patient populations, as determined from several integrated safety studies.

(olil] A total of 2429 subjects were treated with VIT-45 or control agents oyer 10 studies that provide safety data for VIT-45. Of these, 1709 subjectsreceived VITAS (1095 in completed multicenter studies, 584 in placebo-controlled,single-dos, crossover studies and 30 in pharmacokineic studies). The mean total dose of VT-45 administered among the 1095 subjects in the completed multicenterstudies was approxirnately1300 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 I or 2 doses.

£01121 Table 2 provides a summary of VIT-45 studies describedin this example.

[Oat3 Study A was a single-center, single-dose escalationrandomized, double 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 V bolus injection of VIT-45at 100 mg,500mg, 800mg or 1000 mg. Examinedpharmacokineic parameters included total serum iron and pharmacodynamic (serum ferritin and transferrinirn bInding capacity, %TSATpost, hemoglobin, reticulocyte,and serum transferrin receptor concentrations) endpoints.Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, ECG, and physical examinations. £01141 Study B was a single-centersingle-dose, open label, uncontrolled pharmacokinetc study. Subjects were between18 and 75 years of age with fron-deficiency or renal anemia with no other cause of anaemia Inclusion criteriaincluded hemoglobin concentration between 0 and 13g/dL no blood transfusions in the previous 3 months, and no history of treatment withntravenous Iron In the last 2 weeks. Treatment was a single IV bolus injectionof VIT-45 at100 mg labelled with "Fe and Fe. Examinedprimarypharmacokinetic parameters included the distribution of "Fe and incorporation of 6*Fe into red blood cells Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs, and physical examinations. £0115I Study Cwas an open-label multicenter, randomized; multiple-dosesactive controlled postpartum anemia study. Subjects were female, postpartum within10 days after delivery, with hemoglobin 10 g/dL at Baseline based on the average of 2.hemoglobn values drawnl8 hours postpartum. Treatment was once weekly doses of VIT-45 for six weeks VIT 45 dosage was based on the caldulatediron deficit (s2500 mg total). Where screeningserum transferrin saturation (TSAT) was 20% or screening ferritin was 550 ngmL, dosage = pre pregnancy weight (kg) x (15-baseline hemoglobin [gdLJ)x 2A 4500 mg Where screening TSAT was >20% and screening ferritin was >50 ng/mL, dosage = pre-pregnancy weight (kg) x (15-baseline hemoglobin g/dL)x 24. Infusion of VIT-45 was as follows: 200 mg, administered as an undiluted intravenous push (VP) over 1-2 minutes;300-400 mg.administered in 100 cc normal saline solution (NSS) over 6 minutes; 500-1.000 mg administered in 250 cc NSS over 15 minutes, For primary efficacy,"success"was defined as anIncrease in hemoglobinof 2 g/dL anytime between baseline and end of study ortim of intervention, while "failure" was defined as <2 g/dt increase in hemoglobin at all times between baseline and end of study or time of Intervention, Examined safety parameters included adverse events clinical laboratory evaluations, vital signs,and physical examinations

(01163 Study D was a multicenter, open-label, randomized activeontrolledmultiple dose postpartum anemia study, Supjects were adult women a18 years old with pstpartum anaemia within 6 days after delivery. Treatment was administered once-weekyforamaximum of 3 infusions. Patients received IV infusions of 16,7 mUmin to deliver a maximum dose of 1000 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 of 200 mg and a maximum dose of 15 mg 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 anda maximum dose of 1000 mg at each subsequent dosing. Doses of 200-400 mg were diluted in 100 cc NSS and tO 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.

[01173 Study E was a multicenter, open-label, randomized, active-controlled, multiple dose hemodialysis-associated anemia study, Subjects were adult male 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 individual calculated cumulative dose was reached. Patients received 200 mg VIT-45 during their scheduled haemodialysis sessions (2-3 sessions/week) until the calculated cumulative dose was reached. Cumulative totaliron requirement was calculated for each patient using the Ganzoni formula. Primary Efficacy was examined as the percentage of patients reaching an Increasein hemoglobin 10 g/L at 4 weeks after baseline. Examined safety parameters included adverseevents, vital signs, 12-lead ECG, physical examinations, and clinical laboratory evaluations.

[01l8 Study F was amultcenter open-label, multiple dose, uncontrolled hemodialysis-associatd 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 mg VIT-45 during their scheduled haemodialysis sessions (2-3 sessions/week) until the calculated cumulative dose was reached. Cumulative total iron requirement was calculatedfor each patient using theGanzon formula. Efficiceacy 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, hematology and blood chemistry profiles, and urea reduction ratio. 10119) 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 stableiron-deficiency anemiasecondary to a gastrointestinal disorder and a calculated total iron requirement 21000 mg; 50% of patientsin each cohort wereto require ,1500 mg totalIron 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 andpharmacodynamic (hemoglobin, ferritin, TSAT) endpoints, Examined safety parameters included adverse events, clinicallaboratory evaluations, vital signs, ECG physical examinations, andelevated serum ferritin (>500 pg/L) AND elevated TSAT (>45%).

10 [0120] Study H was a multicenter, muliple-dose randomized, open-label, active-controlled gastrointestinal disorderassociated anemiastudy. Subjects weremales and females aged 18 to 80 years, inclusive, with iron-deficiency anaemia secondary to chronic inflammatory boweldisease (ulcerative colitis or Crohn's disease) and a calculated total iron requirement of at least 1000 mg total iron. Treatmentwas weekly VIT-45 infusions, with a 15 maximum of 3 infusions permitted 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 unti 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, 12-lead ECG, physical examinations, and clinical laboratoryevaluations.

(01212 Study I was an open label, multple-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 dosagewas based on the calculated iron deficitas follows: where baseline TSArT:20% or baseline ferritin 50 ng/mL, VIT-4S total dose in mg = baseline weight (kg) x (15 baseline hemoglobin jg/dL) x 2,4 t 500; where baseline TSAT >20% and baseline ferritin >50 ng/mL, VIT-45 total dose in mg = baseline weight (kg) x (15-baseline hemoglobin [g/dLJ) x 2. For administration, s200 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 administered in 250 cc NSS over 15 minutes. Primary efficacy was examined as the proportion of subjects achieving success, defined as an increasein hemoglobin of' 20g/dL anytime between baseline and end of study or time ofintervention. Examinedsafetyparametersincded adverse events, clinical laboratory evaluations, vital signs, and physical examinations

[0122) Study J was a multicenter, single-dose blinded, randomized, placebo controlled crossover iron deficiency anemia study. Subjects were male orfemale, at least 18 years of age, with a hemoglobins12 g/dL, TSAT 25%, and fernitIn <300 ng/mL (iron deficiency anemia due to dialysis or non-dialysis dependent chronic kidney disease or inflammatory bowel disease), orferritinr100 ng/mL(iron-deficiency anemia due to other conditions). Treatment was two single doses seven days apart. Admistration of VIT-45 occurred over 15 minutes and was, 1000mg (15 mg/kg for weight 566kg For pham acokinetic variables, total serum iron was assessed using AtomicAbsorption methodology. Examined safety parameters included adverse events, clinical laboratory evaluations, vital signs and physicalexaminations,

TABLE2 Summary of Safety Studies ofVT-45 Sdyumber Subes nravous Does)orv-or Pannkinee Sudies A Total;32 r"gledoeso acebo VT45; 24 mg via bossinction 300 mg<$00stgO m dilted in 250rmL of NSS$adsnnineredby IYinfusioncives 15 minues ' Totab;6 Single dose of 100 Wg labelled with `Feandf N'oe VITASm 6 administeredasi an V injction over 10 mines

Sudes inSubjiects wi Pospanrm Anrinh C Totalb 52 C dmeU ionr cm qurcmerawascatsete Oralron (rbnoos VIT-4: 174 far ach paesmPaemntes ivedV infusons to sulte) 325 mg TO deliver trasnmdoof1000mig iron per for 6weeks usonPe rceiveA VIT-45 infions once weeily untilthe celcultsedeumiultive dose was raced ormaximum ofr20 mg adbeen admninistoedDoses s200 mg wradmtridMed Spush ver minu s2doses C; or300400i mg were dilued in 100 cc1NSand'dS iniseredover 6rminutesdosessof 500-1000tog weredilutdit i 250c S and dadnistred overiS minues, D JTota: 344 Cumulaivetota iron requirement wascenfated Oral ron(ferous VT-45; 227 ror each patient using the Ganzonifranes. [sulase) 00 rg D j ___________ ______ r fn2 weeks Stdiesin SubjctsJdeon in modlhysis E Tiu 3 PatIents received 200mg VWlosI njion of Venoipaients VITAS: 119 study drug duig beOrscheduledhemodiaysis received200 mg V sessions(243asestnswedl) untilthe cteutated injetion overt10 ctsnbste dose was reachedCumulatve total minuses of study tmnrequiremen was enk]ulated fbreachpale drug during their uagfthlsGOsnzoni forss, scheduled htrnadialysis sessIons(24 sessIons/week) until she calculated cumousdve dos was rahed, utive totalirnn requirement was cakuhatedforeach ptit usiigs he (inzorui rmnua? PTotal;16J Patfents received 200 mgIV push orsudy dug None VlTAS: 162 duringteirscheduLed hemsodialysis sessions (2 3 sessions/wecek) umtilthe calculated cumulaive dosewasreehed, Cumiulativetta iess squirernenwascalculatedforeach paiernusing ______Ste Gnannfonnula,

Swdie e Subjec tswih GstroinestrlDisrdms STota 46 500 mg Or1000 g Ironby IVusion a weekly None Vr-4 46 intevak for upto 4 wcek ($00 m) or 2 weeks (0 00 n)vA wk rs t endose of2000vmg, 'he s dosecould have beenss, deepening onte calculaed total iron requremem. Doses wer diued in25 ccNeNdadministered by IV infusion over 5 intes H Total: 20 Cmutrivetotal ron requrementwasesacuitued OrWion(renm VIT5: 137 forcach patietusing theGanoni annula. Isulfate)100rug D jtr1r weeks Study in Subjem whh Heavy UterineBeding IToth456 t000 mgveak (5 ggfbrweigs6 g f(I k Orai iron(ferrous VITAS;:230 patients received VlT-43 inusionsonce weely slate) 325 mg TiD undilthe ealculaecd cwnat'e dose was reachedoerlihr 6wetks awmaxkmumof 2500rmghad been adinistcend, Dosess$20emg wereadministered Wpush overI 2 minutes; doses of300-40 IweeMdutedin 100 ccNSS and adninistered over minutes; doses oCSOO1000rg were ditndin250 cc NISand adsminserd over15$minutes. StudytinSurbjecis with ron Deiciency Anemia :Toah:594 Singledose ots1000 mgbyPVinflsinoverS P5 acebo V minutes(1$ng4 0 ftr weight 66 kg), Doses $500 mg werdiluead in 1t c NSS and doses of >500,1000ugmwe diluted in250ccNS. Pharmacokineic subjet:single 1,000 mg dose by W infusion

C01231 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%)and Venofer (1.6%) groups. Reasons for premature discontinuation were generally comparable among the treatment groupsexcept that the incidence of adverse events leading to discontinuation were higher in the Venofer group (59%) compared to the V-45 (8%) and oral iron (2.1%) groups, demonstrating the overall tolerability of VIT-45.

toL241 The overall incidences of treatment-emergent adverse events were comparable between the VIT-45(49.5%) and Oral Iron (512%) groups in the completed 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 experienced by 2% of the 1095 VIT45 subjects included headache(&6%). abdominal pain (2.5%), nausea (2.4%), blood phosphate decreased (2.4%), hypertension (22%), nasopharyngitis(2.0%), and hypotension (20%), As expected, the most notable difference 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 observedin the VIT-45 group.

(01251 In the calculated doselfirst-dose 1,000rg studies, nostatistically significant difference was observed between the VIT-45(495%) and oral iron (512%) groups for the overall incidence of treatment-emergent adverse events, The incidence of gastrointestinal disorders - was statistically significantly (p<0.0001) 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 statistically signficantly higher in the VIT-45 group (9.1% and 73%, 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 VT-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 eventsassociated 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 subcutaneoustissue disorders, greater proportions of VIT-45 subjects experienced rash and pruritus than oral iron subjects,

[0126] The 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 reported on the first day of dosing in the calculated dose/first-dose 1,000 mg studies was statistically significant higher inthe VIT-45 group compared to the oral iron group (5,8% 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, primarly events associated with the site of study drug infusion, and skin and subcutaneous tissue disorders, primarily rash and urticaria, compared to the oral fron group. 10127] The overall incidence of treatment-emergentadverse events was similar among VIT45 subjects treated vAth either the 200 mg or 1000 mg doses. The only notable difference was for the higher incidence of headache In the 1000mg group,whIch was almost double that observed for the 200-mg group, No meaningful trends were apparent with respect to the Incidence of treatment-emergent adverse events when analyzed by gender, age, race, weight, or etiology of anemia.

101281 There were no deaths in the study attributed to VIT-45. The incidence of other serious adverse events among VIT-45 subjectswas low (3% in all completed multicenter studies and 0.3% in the placebo-controlled, single-dose crossover study) and none were considered related to study drug. The incidence of premature discontinuation due to adverse eventswas comparable between the VIT-45 group (2,1%) and the other active treatment groups (3,1% orat iron and 2,5% Venofer). The incidence of drug-related treatment-emergent adverse events of hypersensitivity was 0.2%, the same as that observed wh oral iron (0.2%). Drug-related mild or moderate hypotenson was observed in 4 (02%) VIT45 subjects, none of which were considered serious, led to premature discontinuation, orwere symptomatic. Treatment-emergent adverse events indicative of potential allergic reactions including rash, pruritus, and urticaria were reported by <2% of subjectswho 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 parameters evaluated. However, during the conduct of the latter portionof the clinical program, transient asymptomatic decreases li bloodphosphate 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 from the study 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 decreaseIn 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 intrinsic to iron therapy in this severely anemic population. (0130] Overall, no clinically meaningful changes in vitals signs evaluations were associatedwith VIT45 administration.

(0131] Safety data from more than 1700 subjects demonstrate the safety and tolerability of VIT-45,

[0132] A referenceherein to a patent document or other matter which is given as prior art is not taken as an admission that that document or prior awas part ofcommon general knowledgeat the priority date of any ofth claims

[0.133] With reference to the use of the word(s) "comprise" or"comprises" or "comprising" in the foregoing description and/or in the following claims, unless the context requires otherwise,those words areusedonthe basisandclear understandgthat they are to be interpretedinclusively,rather than exclusively andthat eachofthose words is to he so interpreted inconstruing thei oregoing description and/or theifbllowing claims.

Claims (16)

The claims defining the invention are as follows:

1. A method of treating a disease, disorder, or condition characterized by iron deficiency or dysfunctional iron metabolism resulting in reduced bioavailability of dietary iron, comprising: administering to a subject in need thereof an iron carbohydrate complex in a single dosage unit of at least 1.1 grams of elemental iron; wherein the iron carbohydrate complex: is an iron polyisomaltose complex; has a substantially non-immunogenic carbohydrate component; has substantially no cross reactivity with anti-dextran antibodies; comprises an iron core having a mean iron core size of at least about 1 nm but no greater than about 9 nm; and wherein the subject does not experience a significant adverse reaction to the single dosage unit administration.

2. A method of claim 1, wherein the single dosage unit of elemental iron is: i) at least 1.1 grams to about at least 2.5 grams; or ii) at least about 1.1 grams to at least 1.5 grams; or iii) about 1.5 grams; or iv) at least 1.5 grams; or v) up to about 2.0 grams.

3. The method of claim 1 or claim 2, wherein the iron carbohydrate complex contains about 24% to about 32% of elemental iron.

4. The method of any one of claims 1 to 3, wherein the iron carbohydrate complex has a pH from about 5.0 to about 7.0.

5. The method of any one of claims 1 to 4, wherein the iron carbohydrate complex has physiological osmolarity.

6. The method of any one of claims 1 to 5, wherein the disease, disorder, or condition comprises anemia.

7. The method of claim 6, wherein the anemia comprises iron deficiency anemia.

8. The method of claim 6, wherein: (i) the anemia comprises an iron deficiency anemia associated with chronic blood loss; anemia associated with acute blood loss; anemia associated with pregnancy; anemia associated with childbirth; anemia associated with childhood development; anemia associated with psychomotor and cognitive development in children; anemia associated with breath holding spells; anemia associated with heavy uterine bleeding; anemia associated with menstruation; anemia associated with chronic recurrent hemoptysis; anemia associated with idiopathic pulmonary siderosis; anemia associated with chronic internal bleeding; anemia associated with gastrointestinal bleeding; parasitic infections; anemia associated with chronic kidney disease; anemia associated with dialysis; anemia associated with surgery or acute trauma; anemia associated with chronic ingestion of alcohol; anemia associated with chronic ingestion of salicylates; anemia associated with chronic ingestion of steroids; anemia associated with chronic ingestion of non-steroidal anti-inflammatory-agents, or anemia associated with chronic ingestion of erythropoiesis stimulating agents; (ii) the anemia associated with a chronic disease selected from the group consisting of anemia associated with rheumatoid arthritis; cancer; anemia associated with Hodgkins leukemia; anemia associated with non-Hodgkins leukemia; anemia associated with cancer chemotherapy; anemia associated with inflammatory bowel disease; anemia associated with ulcerative colitis thyroiditis; anemia associated with hepatitis; anemia associated with systemic lupus erythematosus; anemia associated with polymyalgia rheumatica; anemia associated with scleroderma; anemia associated with mixed connective tissue disease; anemia associated with Sojgren's syndrome; anemia associated with congestive heart failure/cardiomyopathy; and idiopathic geriatric anemia; (iii) anemia associated with impaired iron absorption or poor nutrition; (iv) anemia associated with Crohn's Disease; anemia associated with gastric surgery; anemia associated with ingestion of drug products that inhibit iron absorption; or anemia associated with chronic use of calcium.

9. The method of any one of claims 1 to 7, wherein the disease, disorder, or condition is selected from the group consisting of anemia associated with restless leg syndrome; anemia associated with blood donation; Parkinson's disease; anemia associated with hair loss; and anemia associated with attention deficit disorder.

10. The method of any one of claims 1 to 7, wherein the disease, disorder, or condition is anemia associated with congestive heart failure/cardiomyopathy.

11. The method of any one of claims 1 to 10, wherein the single dosage unit of elemental iron is administered in about 15 minutes or less.

12. The method of any one of claims 1 to 10, wherein the single dosage unit of elemental iron is administered in about 5 minutes or less.

13. The method of any one of claims 1 to 12, wherein: the mean iron core size is at least about 1 nm but no greater than about 9 nm; or the mean size of a particle of the iron carbohydrate complex is no greater than about 35 nm.

14. The method of any one of claims 1 to 13, wherein the iron carbohydrate complex is administered parenterally.

15. The method of claim 14, wherein: (i) parental administration comprises intravenous infusion and the single unit dose of iron carbohydrate complex is administered at a concentration of about 1000 mg elemental iron in about 200 ml to about 300 ml of diluent; (ii) parenteral administration comprises bolus injection and the single unit dose of iron carbohydrate complex is administered at a concentration of about 1000 mg elemental iron in about 200 ml to about 300 ml of diluent; or (iii) parenteral administration comprises intramuscular injection and the single unit dose of iron carbohydrate complex is administered at a concentration of about 500 mg elemental iron in less than about 10 ml diluent.

16. The method of any one of claims 1 to 15, further comprising a second administration of said iron carbohydrate complex upon recurrence of at least one symptom of the disease, disorder, or condition.