US Uniferon Handbook by Pharmacosmos

The Uniferon Handbook ÂŽ

An accurate pen-side diagnostic tool for use in determining an effective dosage of UniferonÂŽ 200 for the prevention and treatment of sub-clinical and full-scale iron deficiency anemia.

Table of Contents Introduction and the F.A.C.T Program About this diagnostic tool..............................................................3 About Pharmacosmos and UniferonÂŽ 200..................................4-5 What is the F.A.C.T program and its benefits?...........................6-7 Industry-Accepted Iron Standards Why optimal Hemoglobin (Hb) blood levels make a difference..... 8 Benefits of optimal hemoglobin blood levels.................................9 Are your baby pigs at risk of entering an iron gap?..................... 10 Benefits of second iron injection.................................................. 11 Iron Deficiency Anemia Detection and Treatment How do you know if a baby pig is suffering from anemia?.....12-13 How iron treatment sources differ................................................14 The benefits of injection and technique..................................15-16 Every drop counts..................................................................17-18 When and how to select baby pigs for evaluating herd hemoglobin blood level status.......................................................... 19 How to test your selected baby pigs............................................20 Pen-side blood testing for diagnosis of sub-clinical and full-scale iron deficiency anemia............................................21-23 Other Anemia Contributors and Conditions What if my baby pigs get infected with a virus?.....................24-25 About vitamin E deficiency..........................................................26 About mycotoxins in swine feed..................................................27 Resources and References UniferonÂŽ benefits........................................................................28 Iron expert board.........................................................................29 Pharmacovigilance associated with the prevention and treatment of sub-clinical and full-scale iron deficiency anemia... 30 The basics of adverse events associated with the administration of parenteral iron supplementation...................... 31 Resources and references.....................................................32-33 Contacts......................................................................................34

About this diagnostic tool This accurate pen-side diagnostic tool enables the modern swine production operations to evaluate and treat their baby pigs with an effective follow-up dosage of Uniferon® 200 mg/mL that will prevent or treat sub-clinical or full-scale iron deficiency anemia.

What you will find on the following pages: • Information on our F.A.C.T iron deficiency anemia assessment program • How and why pigs may become subject to sub-clinical or full-scale iron deficiency anemia • Industry-accepted iron level standards • How to clinically assess a herd • Effective Iron treatment program and administration • Best practices

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About Pharmacosmos Pharmacosmos is the leading manufacturer and developer of prevention and treatment of iron deficiency anemia in humans and animals. Our Uniferon速 (Iron (III) Dextran) product is the only prevention and treatment of baby pig anemia approved by health authorities in Europe, Asia and by FDA in the U.S. Uniferon速 200 mg/mL is manufactured according to highest quality in our manufacturing facilities in Denmark. Pharmacosmos works closely with pork producers, swine veterinarians and partners around the world to incorporate best practice solutions into our treatments and treatment with the proper administration of Uniferon速 200 mg/mL is a simple way to realize higher production yields and higher profits.

Learn more about Pharmacosmos, the manufacturer of Uniferon速 200 mg/mL, which is the leading world-wide prevention and treatment product for sub-clinical and full-scale iron deficiency anemia in baby pigs.

Learn more - visit www.pharmacosmos.com

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About Uniferon® 200 Uniferon® 200 mg/mL from Pharmacosmos is an injectable iron supplement for baby pigs that promotes better health and faster growth.

It is well known that injectable iron supplementation of baby pigs via injection of 200 mg/mL iron during processing on days 1 to 3 post-farrowing has become the industry standard for prevention or treatment of sub-clinical or full-scale iron deficiency anemia.

Uniferon® 200 mg/mL is the only world-wide brand of injectable iron that is successfully utilized for the prevention and treatment of sub-clinical or full-scale iron deficiency anemia, whereby: • It boosts and maintains optimal hemoglobin levels1; • It ensures optimal average daily gain (ADG)1; • It promotes more rapid post-weaning growth1,3; • Uniferon® 200 mg/mL is fully absorbed, and it supports a high-level target animal safety profile7; • It has received global approvals from numerous healthcare authorities; and • Uniferon® 200 is the only 200 mg/mL CVM/FDA approved injectable iron product in the U.S. veterinary market.8

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What is the F.A.C.T program?

Our F.A.C.T program has been designed to provide a 360º view of the iron status of baby pigs on the modern swine production operation. In close cooperation with production managers and swine veterinarians, the F.A.C.T program: • Provides an overall perspective of the production facility and the influencing factors that impact the iron status in baby pigs • Introduces an accurate and convenient pen-side diagnostic test for sub-clinical or full-scale iron deficiency anemia in baby pigs • Provides a timely and accurate diagnosis for potential sub-clinical or full-scale iron deficiency anemia in individual baby pigs, which will help to rapidly depict the iron status of the other litters in the herd as well • Eliminates the guesswork of iron status in baby pigs and reduces the risk of misdiagnosis of sub-clinical and full-scale iron deficiency anemia • Provides a progressive approach and includes swine industry best practices • Provides the injectable iron knowledge resources for the industry The acronym F.A.C.T stands for

Farm Anemia Certification and Training

F.A.C.T

Enrolling in F.A.C.T is easy by emailing uniferon.us@pharmacosmos.com

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What are the F.A.C.T benefits?

F.A.C.T has benefits for swine producers and provides access to a large data base of information and the support to begin making a significant difference in your herd. Do not leave your baby pigs at risk of misdiagnosis. Be certain about your herd’s iron status by implementing the F.A.C.T program today.

Our F.A.C.T program has three key features: Assessment • Accurate and convenient pen-side blood hemoglobin measurements • Hemoglobin blood level assay results within 30 seconds • Tools for getting started Training • Education on role of iron in physiology • Calculating iron requirements of individual baby pigs • Baby pig handling • Iron administration/injection techniques • Field training for staff, advisors and consultants Overview • 360º overview of welfare and health status of baby pigs • Access to open scientific literature and market research reports • Conducting on-site clinical trials and studies as necessary 7

Why optimal hemoglobin (Hb) blood levels make a difference Anemia is a condition which results in a lack of iron-carrying hemoglobin in the red blood cells. It typically occurs when the baby pig’s iron stores are depleted by rapid growth on an all-milk diet or when the exposure to stress conditions either inhibits the build-up of hemoglobin or increases the degradation of hemoglobin in the blood stream of the baby pig. Iron deficiency anemia is either a sub-clinical condition, or a clinical manifest condition known as full-scale iron deficiency anemia.

Hemoglobin is a critical iron-rich protein that enables red blood cells to carry oxygen throughout the body. Also, hemoglobin carries carbon dioxide to the lungs for release and exit from the body, which enables the hemoglobin to transport more oxygen throughout the body. Hemoglobin, along with myoglobin, are two proteins that require adequate levels of iron to optimize growth and support immune system development. Clinical benchmarks for optimal hemoglobin levels and the relationship to baby pig sub-clinical or full-scale iron deficiency anemia are delineated below: <90 = Clinical anemia* 90-110 = Sub-clinical >110 = Optimal For optimal baby pig health and performance, hemoglobin levels must be at or above 110 g/L2

Thorn CE. Hematology of the pig. In: Weiss DJ, Wardrop JK, eds.

Schalmâ&#x20AC;&#x2122;s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-Blackwell; 2010:843 *

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Benefits of optimal hemoglobin blood level Elevated hemoglobin levels are important as these are known to further benefit oxygen transport, immune function, vitality and metabolism in baby pigs. A recent study has shown remarkable associations of the hematological status at weaning and the weight gain post-weaning. Industry experts believe that optimized postweaning growth requires hemoglobin levels at or above 110 g/L.2 It has been demonstrated that increasing blood levels of Hb were positively associated with growth rates of baby pigs post-weaning (p=0.0003, estimate=1.8 g ADG/gHb/L). Thus, a variation of 10 g/L in hemoglobin at weaning results in a variation of 18 g/day in weight gain 3 weeks after weaning.3

Estimated ADG (oz/day)

10.6 8.8 7.0 5.3 3.5 1.7 0 70

80

90

100

110

Hb

120

130

140

150

In other words, when the pre-weaning blood hemoglobin levels are increased by 10 g/L, the post-weaning weight gains are increased by 18 g/day.

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Are your baby pigs at risk of entering an iron gap?

300

200 mg administration (day 1-3)

250 200 150

Second administration (before day 17)

100

-100 -150 -200

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02 5 10 9 .1 10 6 .7 11 4 .3 11 1 .8 12 8 .4 13 6 .0 13 3 .6 14 0 .1 14 7 .7 15 5 .3 15 0 .8 16 7 .4 17 5 .0 17 2 .5 18 9 .1 18 7 .7 4

87

9.

9.

30

75

8.

7.

17

7.

56

03

6.

6.

45

5.

88

5.

4.

3.

0 -50

31

50 3.

Hypothetical model for Iron Gap5

Fe 3+ reserve (mg)

Improved weight gains on an all-milk ration increase the risk of developing sub-clinical or full-scale iron deficiency anemia and, hence, may well prevent optimal weight gains as well. This increased productivity can contribute to a potential “iron gap” due to the depletion of iron stores from birth and low levels of iron in the sow’s milk (approximately 1 mg of daily intake), which are known to have diminished to even lower levels due to increased litter sizes.4

Point where iron requirements exceed availability

-250 Iron consumption in relation to growth

“Iron Gap”

Pounds body weight (lb)

Calculate baby pig iron requirements in order to avoid entry to an iron gap Visit us.uniferon.com/iwgo/US in order to locate a convenient iron calculator to help you with the assessment of optimal iron requirements for your baby pigs.

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Benefits of second iron injection A single 200 mg dose of injectable iron for baby pigs administered on days 1 to 3 post-farrowing accommodates approximately 8.8 lb of weight gain on an all-milk diet. A follow-up dose of 200 mg of injectable iron on or about day 14 is recommended to help meet growth demands for the next 8.8 lb of weight gain for baby pigs on an all-milk diet.5 Recent on-site clinical trial data reveals increased weight gain and hemoglobin blood levels in baby pigs when treated with a second 200 mg/mL dose over baby pigs provided only a single dose.1

325

306 2 injections of Uniferon® 1 injection of Uniferon®

Day 34-50 (post weaning)

Hemoglobin (g/L)

Weight gain (g/d)

Effect of second Uniferon® 200 mg/mL injection

123

113

Day 34 (at weaning)

(Weight gain and blood hemoglobin results show statistical significance of p=0.01* and p=0.0001*** respectively)

Administration of a second dose of injectable iron prior to weaning has shown benefits in growth rates and overall performance, especially in baby pigs exceeding 8.8 lbs of weight gain on an all-milk diet post-farrowing.1, 6

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How do you know if a baby pig is suffering from sub-clinical or full-scale iron deficiency anemia?

Sub-clinical iron deficiency routinely goes unnoticed because it is nearly impossible to diagnose using only clinically observed symptoms; however, full-scale iron deficiency anemia is detectable using only clinical symptoms, while the baby pig health conditions are often times quite severe before being noticed. Therefore, testing for blood hemoglobin levels allows practical and early detection of sub-clinical iron deficiency in baby pigs, allowing swine producers to administer additional supplemental injectable iron in order to treat the sub-clinical iron deficiency, and virtually eliminate the development of full-scale iron deficiency anemia in baby pigs.

Pen-side or laboratory evaluation of the hemoglobin level in a blood sample taken from a vein will indicate whether or not the baby pigs are suffering from sub-clinical or full-scale iron deficiency anemia.

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First signs of anemia: • Poor growth • Paleness of the mucous membranes Severe signs of anemia: • Listlessness (baby pigs are slow to move, appear to be tired and listless and remain lying down) • Rough hair coat and wrinkled skin • Labored breathing (for example, baby pigs are virtually out of breath during weaning day movement to the transport truck) • Increased heart rate • Increased respiratory rate or spasmodic movement of the diaphragm muscles following minimal exercise, for example, baby pigs that are gasping for air with minor levels of exercise, which is especially noticeable when walking a rather short distance to a transport truck on weaning day movement to the nursery Once visual signs of anemia are detected using only clinically observed symptoms, the immune system status and the growth rates of baby pigs have already been quite significantly, and adversely affected.

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How iron treatment sources differ Colostrum and milk from the sow are both good sources of iron; however, the iron concentration levels in these two sources are inadequate to support optimal growth. Therefore, iron supplementation is required.

Iron from the sow Swabbing the sowâ&#x20AC;&#x2122;s udder with an iron-rich solution is a relatively poor option, because baby pigs are unable to effectively absorb and assimilate oral iron as hemoglobin into the bloodstream, and it is typically too labor intensive to be a cost effective, or a long-term solution to sub-clinical or full-scale iron deficiency anemia in baby pigs.4 Iron from the environment Baby pigs in confinement at commercial swine production operations have little, if any, access to natural soil habitat, whereby the innate rooting behavior of the species could provide a potential source of oral iron and other minerals.4 Parenteral iron supplementation Supplementation with injectable iron is widely recognized as the most practical, cost-effective, accurate dosing and effective method of prevention or treatment of sub-clinical and full-scale iron deficiency anemia in baby pigs.4 Oral supplementation The ultimate challenge for success with orally administered iron supplements is the inefficient absorption of the iron from the immature gut of baby pigs. Furthermore, with oral iron supplementation only, there is considerable animal to animal variation in the poor absorption and assimilation of the oral iron, which provides minimum to virtually no absorption and utilization of the oral iron supplement.4

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The benefits of injection Parenteral administration Once again, the most practical, cost-effective, accurate dosing and effective method of providing supplemental iron to baby pigs is via injectable administration. With proper injection technique, a single 200 mg dose of supplemental iron at 1 to 3 days of age offers the following advantages:4 • Accurate dosing • Optimal efficacy and weight gain • Cost-effective labor inputs with dosing of baby pigs between 1 and 3 days of age • Minimized risk of sub-clinical or full-scale iron deficiency anemia • Supports optimum growth rates of baby pigs on an all-milk diet • Enhanced immunity and improved general health of baby pigs Administering a single 200 mg dose of injectable iron to all baby pigs at 1 to 3 days of age can prevent or treat sub-clinical or full-scale iron deficiency anemia that may result from low levels of iron available at birth.

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Injection technique For successful prevention or treatment of sub-clinical or full-scale iron deficiency anemia, it is important to practice correct injection technique. This is necessary in order to ensure that the iron is dosed correctly and that the iron supplementation enters the blood stream effectively via absorption from the injection site tissue.

Otherwise you will likely experience anemia in the baby pigs.

Be certain that all involved persons are aware of the proper injection techniques to help ensure optimal iron supplementation.

1. Injection site.

In the U.S., Uniferon® 200 mg/mL is labeled for intramuscular injection into the back of the ham. Place tension on the skin over the rear of the ham and inject to a depth of Site of half an inch, or Injection slightly more.

2. Check that the injection site is clean and dry. If the baby pig’s skin is dirty or wet, wipe it clean with cotton wool soaked in surgical spirits.

Allow the skin to dry before making the injection.

3. Use a small needle.

Uniferon® recommends a 20 gauge 5/8 inch needle that has been sterilized.

4. Pull skin slightly forward before inserting the needle.

5. Quickly and firmly insert the needle.

6. Release the skin, give the injection, and remove the needle. The skin then springs back in place, covers the hole in the muscle and seals the injected material in place, minimizing the risk of leakage.

7. Change needles after every ten baby pigs or after each litter.

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Every drop counts A high degree of mental concentration and attention-to-detail discipline during the supplemental injectable iron administration determines the degree of success in the delivery of an accurate dosage of iron.

Biological scientists generally consider 1 drop of liquid equivalent to roughly 0.05 mL, which means that 1 mL of liquid is comprised of 20 drops of liquid. With a 200 mg/mL injectable iron product, each 0.05 mL drop contains about 10 mg of iron.

Therefore, if a total of 4 drops of a 1 mL accurately measured dosage of the injectable iron product is inadvertently lost on the ground, or leaks back on the needle track and falls to the ground during the dosing procedure, this corresponds to approximately 40 mg of the desired dosage being lost (a 20% loss), and the success of the dosage is thus reduced to 80%. Meanwhile, an accurate delivery of the entire 200 mg dosage of supplemental iron provides the best assurance for the prevention or treatment of sub-clinical or full-scale iron deficiency for your baby pigs.

Continued on next page.

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When swine producing operations choose to administer a 100 mg/mL injectable iron supplement product to baby pigs, there are several challenges that can occur, including the following: • Insufficient amount of iron for baby pigs fed on an all-milk diet • With the administration of a single 2 mL dosage of the 100 mg/mL product, there is likely to be an increased rate of backflow and leakage from the injection site via the needle tracks • With the administration of two separate 1 mL doses of the 100 mg/mL product, there could be an increased risk of injection site trauma due to the two separate injections. Similarly, the two separate 1 mL injection sites for administration of a 200 mg dosage of iron using a 100 mg/mL supplemental iron product increases the risk of neurological injury from a second injection site, and trauma associated with the extra handling of the baby pigs during the second injection.

Meanwhile, • Losing just a single drop of Uniferon® 200 mg/mL during the dosing procedure means losing about 10 mg of supplemental iron that a baby pig will not be able to absorb or assimilate as hemoglobin in the blood stream to be used to prevent or treat sub-clinical or full-scale iron deficiency anemia.

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When and how to select baby pigs for evaluating herd hemoglobin blood level status Iron supplementation dosage regimens for baby pigs are most often very standardized with little focus on variations in birth weight, growth rate or weaning age in individual herds.

When should hemoglobin levels be evaluated in baby pigs?

The industry standard involves a 200 mg dosage of supplemental iron between 1 to 3 days of age without testing for hemoglobin; however, a critical time for the development of sub-clinical or full-scale iron deficiency anemia is a few days prior to weaning.

This situation occurs after the maternal iron transferred to the baby pigs at birth, the iron absorbed from the milk during the lactation phase of growth, and the initial 200 mg dosage of supplemental iron sources have all been depleted during the weight gain on an all-milk diet. Due to the immaturity of the gut of the baby pigs up until the time of weaning, uptake of iron from feed or other oral sources is still of minor importance.

How should one select baby pigs for hemoglobin evaluation?

To determine an overall prevalence of sub-clinical or full-scale iron deficiency anemia within a herd, blood samples should be taken from random baby pigs in random litters within the oldest litters of baby pigs in the farrowing unit.

In a herd with 5% of animals suffering from sub-clinical or full-scale iron deficiency anemia (<90 g Hb/L) a sample size of 20 animals should be sufficient to determine the prevalence of the deficiency with an allowable error of Âą 10%.

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How to test your selected baby pigs To determine the prevalence of sub-clinical or full-scale iron deficiency anemia within the herd, a hematological examination is needed. Hematological examinations can be done by handheld photometer or a reference laboratory.

Method 1 - pen-side testing using Hb photometer: A single drop of blood is taken from the ear vein with a simple pin prick. The blood is introduced into a disposable cuvette by capillarity and then placed in the Hb photometer. Results for hemoglobin concentration are obtained in less than a minute.

Method 2 - lab testing using vacutainer tube: After placement of the baby pig to be tested in a dorsal recumbency position, an approximately 3 mL blood sample is withdrawn from each baby pig by puncture of vena cava or the jugular vein using an EDTA stabilized vacutainer tube. You should ice down the blood samples immediately following the sample collections, being careful not to obscure the label identification thereof, or contaminate the blood samples in the process. The blood samples, thus collected and iced down, should be moved to refrigerated storage for safe keeping until ice-packed and shipped out to the testing laboratory. Laboratory testing for hemoglobin concentration by an independent testing laboratory should be conducted as soon as possible, but in any event should be completed within a 24-hour time frame following the blood sample collections.

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Pen-side blood test for diagnosing sub-clinical and full-scale iron deficiency anemia Measuring the hemoglobin with the handheld device HemoCue 201+ Hb photometer is a fast and reliable way to determine the prevalence of sub-clinical and full-scale iron deficiency anemia within the herd.9 Blood sampling for pen-side testing using HemoCue 201+: The HemoCue 201+ Hb photometer is technically and economically well suited for pen-side hemoglobin examination.

1. A single drop of blood is taken from the baby pigs to be tested by puncturing the ear vein; 2. The blood samples are introduced one-at-a-time into the disposable cuvettes; 3. The cuvettes are placed one-at-a-time into the HemoCue 201+ Hb photometer; 4. The individual assay results for the baby pigs being tested for blood hemoglobin concentration are each successively obtained in less than a minute after the blood samples are collected.

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Assay laboratory testing for diagnosing sub-clinical or full-scale iron deficiency anemia If blood samples are drawn by puncture of the vena cava or the jugular vein, some additional and important assay parameters may be obtained.

Collect a 3 mL sample of whole blood from each of the baby pigs to be tested in EDTA stabilized and plain vacutainer tubes that will need to be iced down immediately after collection, and moved to refrigerated storage for safe keeping until ice-packed and shipped out for assay by an independent testing laboratory. The testing should be conducted as soon as possible, but in any event should be completed within a 24-hour time frame following collection of the blood samples.

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Tests

Significance

Blood hemoglobin

Measurement of Hb in blood

Hematocrit

Measures volume % of RBC in blood

TIBC

Measures bloodâ&#x20AC;&#x2122;s capacity to bind iron with transferrin

Notes

Blood hemoglobin assay results for baby pigs from birth to weaning can be utilized to determine a strategy for ÂŽ Assay Values between 90 to 110 dosing of Uniferon 200 mg/mL that will prevent g/L are indicative of sub-clinical or treat sub-clinical or IDA; and full-scale IDA. Assay Values >110 g/L are indicative of optimal blood hemoglobin levels.

Assay Values <90 g/L are indicative of full-scale Iron Deficiency Anemia (IDA);

Neither blood hemoglobin or hematocrit assay values should be used Measurement of packed cell vol- as single diagnosis test ume requires the determination parameters; however of the volume occupied by RBC when these two test after whole blood is centrifuged parameters are used in for approximately 6 minutes. conjunction, they are A normal value is 0.45 L/L powerful tools for use in diagnosis of sub-clinical Values within a descending and full- scale IDA. range of 0.41 to 0.26 L/L are indicative of sub-clinical or full-scale IDA, respectively.

Indicates % of iron bound

Values within the range of 104-188 mmol/L are indicative of IDA

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What if my baby pigs get infected with a virus?

In many herds, the presence of a viral infection such as porcine reproductive and respiratory syndrome (PRRS) or porcine circovirus type 2 (PCV2) could represent overall health conditions that are conducive to the development of sub-clinical and/or full-scale IDA due to immunosuppression, in spite of the baby pigs having received appropriate injectable iron supplementation.

Trial results demonstrate increased weight gains and blood hemoglobin levels in viremic baby pigs treated with two 200 mg doses, versus the placebo baby pigs treated with only one 200 mg dose.6 Effect of a second UniferonÂŽ injection in immunosuppressed pigs

Weight gain (g/d)

473

2nd UniferonÂŽ injection Saline injection

Day 12-32

6.38

Hemoglobin (mmol/L)

6.62

523

Day 12-32

(Weight gain and blood hemoglobin results show statistical significance p=0.01*)

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• Sub-clinical and full scale IDA in baby pigs are conditions that are exacerbated due to viral infections • Adequate iron supplementation will likely require initial and follow-up injectable dosages that will support subsequent increases in blood hemoglobin levels in baby pigs, which will be quite helpful to the overall health conditions of the baby pigs in the presence of a viral infection • It appears that the follow-up doses of injectable iron enable the baby pigs to develop some measure of damage control when challenged with the immunosuppressed conditions encountered during viral infections.

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What about vitamin E deficiency in the sows and their baby pigs?

As the nutritional status of the sow is the determinant for the vitamin E blood level for the baby pigs, management factors that optimize the vitamin E blood level for the sows are of significant importance and will help prevent the development of sub-clinical or full-scale IDA. The sow’s ability to absorb and transfer vitamin E to the milk varies somewhat from animal to animal. Variation in vitamin E uptake is also seen among baby pigs, and may even vary within the same litter of baby pigs.

I f the sows are vitamin E deficient this approach is recommended:

• Analyze and control the feed content of vitamin E

• Make sure that the gestation feed mixture contains a minimum of 80 mg Vitamin E / Fes and that the lactation feed mixture contains a minimum of 92 mg Vitamin E / Fes, where Fes is defined as feeding unit for swine

• Up to 250 mg/sow/day of the synthetic vitamin E (acetate bound) may be added to the gestation and lactation rations, but in those instances should be the only source of vitamin E supplementation

If the baby pigs are vitamin E deficient this approach is recommended:

• Provide natural vitamin E (peroral administration) to each baby pig. It is recommended to use natural vitamin E for improved bioavailability 26

What about mycotoxins in swine feed?

There are various conditions which can cause iron absorption in pigs to be reduced. One of them is mycotoxins induced “sub-clinical or full-scale iron deficiency” anemia.

Mycotoxins in feed Presence of Mycotoxins in swine feed is a well-known, world-wide problem, and it is much more prevalent in humid climates. For example, Fusarium toxins that develop in crops standing in the wet fields prior to harvest are transferred to the swine feeds. These toxins are not easily detoxified when consumed in swine rations, thus, swine production is decreased.

The reason for the reduced swine production is that the mycotoxins weaken the immune system, interfere with the operation of vital organs and inhibit the bone marrow production of RBCs, which leads to sub-clinical or full-scale IDA. The presence of mycotoxins in swine feeds not only weakens the immune system of the sows, but it may also prevent the uptake and assimilation of vitamin E in the feed. As vitamin E is essential for the uptake and assimilation of iron in both sows and baby pigs, the mycotoxins induced development of sub-clinical or full-scale IDA is enhanced by the reduced absorption of vitamin E in the sow’s ration.

In order to solve the mycotoxins problem, we recommend tracing the sources of the mycotoxins to particular feed components, the use of a mycotoxins mitigating substance to help prevent and/or offset the negative effects of molds and mycotoxins and additionally improve gut health.

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Uniferon® 200 benefits • Uniferon® 200 mg/mL injectable iron supplement has been proven to be quite beneficial for the prevention or treatment of sub-clinical and full-scale IDA • Uniferon® 200 mg/mL has been research-proven to optimize blood hemoglobin levels and average daily gain • Uniferon® 200 mg/mL is the only iron supplement supported by research trials on a world-wide basis • Uniferon® 200 mg/mL complies with the highest quality standards of identity, strength, quality and purity, which also includes the elements of safety and efficacy, and it has approved registrations in Europe, Asia and North America (including FDA approval for use in the United States veterinary market) Uniferon® is the #1 injectable iron supplement in the world

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Iron Expert Board Pharmacosmos has established the Iron Expert Board (IEB) with a dedicated panel of experts that consists of international Key Opinion Leaders, which represent some of the most widespread and up-to-date swine production experiences and the best intellectual aptitudes in the field of baby pig health and iron supplementation.

The goal of the IEB is: • To ensure adequate iron supplementation for all baby pigs, thus, avoiding the “iron gap” • To widen the full understanding of sub-clinical and full-scale IDA, and the direct relationship between the optimization of blood hemoglobin and the optimization of growth and weight gains in baby pigs • To avoid inappropriate use of iron and toxic conditions encountered during “iron overload” • To make up-to-date recommendations for injectable iron supplementation for baby pigs in order to prevent or treat sub-clinical and full-scale IDA

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Pharmacovigilance Each national health care system has a pharmacovigilance system associated with the prescription and administration of medicines in humans and animals, which ensures a satisfactory handling of adverse events in compliance with local laws and guidelines.

Pharmacosmos has the overall responsibility for maintaining a highly compliant and skilled safety surveillance for Uniferon®.

Pharmacosmos has organized worldwide reporting of adverse events via Uniferon® partners that operate within compliance of local health care regulations. In parallel, Pharmacosmos systematically reviews the worldwide scientific literature for the Uniferon® product and is responsible for signal detection.

Comparison over time of the ratio of animals reported for adverse events/ lack of efficacy (ABON, including 01)7 Ratio (number of animals/number of doses)

0.0002%

0.00003%

Periodic Safety Update Report (PSUR) Product: Veterinary iron dextran, solution for injection Period of reporting: August 1, 2009 – July 31, 2012

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The basics of adverse events associated with the administration of parenteral iron supplementation Intramuscular injections of parenteral iron products, in general, may cause transient discoloration/calcifications at the injection site, or hypersensitivity reactions normally considered non-serious adverse events.10 Intramuscular injections of parenteral iron products can very rarely cause a serious adverse event (deaths).

The most likely reasons for a serious adverse events following the administration of parenteral iron products are listed below:10 • Exposure to an intravenous injection • Iron shock associated with genetic factors • Vitamin E and/or selenium deficiencies • Contamination with Clostridia bacteria due to improper handling/ storage conditions The Active Pharmaceutical Ingredient (API) manufactured by Pharmacosmos is a 200 mg/mL solution of iron dextran.

On the rare occasion of an adverse event, the elimination of any likelihood of production related failure is of great concern to Pharmacosmos, whereby all possible scenarios are thoroughly evaluated in conjunction with any adverse event. Maximum care and caution have been exercised in Uniferon® 200 mg/mL manufacturing to achieve European MRP10 approval and FDA approval in the U.S.8 31

Resources To learn more about our UniferonÂŽ 200 mg/mL product, please visit our online Q&A link: us.uniferon.com/questions-and-answers If you are interested in learning more about sub-clinical and full-scale iron deficiency anemia, please visit our online Learning Center: www.uniferon.com/learning-center Determine the potential mean iron need within a litter of baby pigs with our online Iron/Weight Gain Optimizer (I/WGO): www.uniferon.com/iwgo/US

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References 1 Haugegaard, J. et al., 2008: ”Effect of supplementing fast-growing, late-weaned piglets twice with 200 mg iron dextran intra-musculary” The Pig Journal (2008) 61, 69 – 73 2 Nielsen, J.P. et al., 2013: “Herd diagnosis of iron deficiency in piglets”.

In: Proc. 5th ESPHM Cong., May 2013 3 Nielsen, J.P. & S. Bhattarai 2014: “Association of hematological status at weaning and weight gain post-weaning in piglets.”

In: Proc. 23rd IPVS Cong., June 2014 4 Gaddy, H.J. et al., 2012: “A review of recent supplemental iron industry practices and current usage of Uniferon® (iron dextran complex injection, 200 mg/mL) in baby pigs”. In: Proc. 43rd AASV Cong., March 2012 5 Van Gorp, S. et al., 2012: “Preventing iron deficiency by avoiding an iron gap in modern pig production”. In: Proc. 43rd AASV Cong., March 2012 6 Bach, J. et al., 2006: ”Effect of an additional iron injection in a PMWS positive herd in respect to hematocrit, hemoglobin and growth rate”.

In: Proc. 19th IPVS Cong., June 2006 7 Periodic Safety Update Report (PSUR); Product: Veterinary iron dextran, solution for injection; Period of reporting: 01.08.2009 – 31.07.2012 8 NADA 134-708: Uniferon® 200 (Iron Dextran Complex, Injection, 200 mg/mL x 100 mL product) 9

h ttp://www.hemocue.com/

10 Procedure No. DK/V/0114/01/MR

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Contacts If you have any questions, or want to share your thoughts or advice, we would like to hear from you.

E: uniferon.us@pharmacosmos.com Corporate contact: Pharmacosmos, Inc. 776 Mountain Boulevard Watchung, NJ 07069 United States T: (908) 769-7045 F: (908) 769-7046

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T: (908) 769-7045 E: uniferon.us@pharmacosmos.com

Quality iron for your baby pigs T: (908) 769-7045 E: uniferon.us@pharmacosmos.com

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UniferonÂŽ is the #1 injectable iron supplement in the world