Feromiel

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Feromiel uses

Feromiel consists of Honey, Iron (Ferrous Pidolate).

Honey:


WARNINGS

This product is intended for use only by licensed medical personnel experienced in administering allergenic extracts and trained to provide immediate emergency treatment in the event of a life-threatening reaction.

Hymenoptera Venom extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death.(1) Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction. Patients should be instructed to recognize adverse reaction symptoms, observed in the office for at least 30 minutes after skin testing or treatment, and cautioned to contact the physician's office if symptoms occur. See ADVERSE REACTION, Section 4, of this instruction for information regarding adverse event reporting.

All patients should have available an Emergency Anaphylaxis Kit containing epinephrine and be instructed in its use for emergency treatment of possible systemic reactions occurring at times after the patient has departed the testing or treatment premises. Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.(1)

Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.(2)

Immunotherapy for insect sting allergy should be given to those patients who have experienced significant systemic reactions (for detailed description of symptoms see INDICATIONS AND USAGE and ADVERSE REACTIONS) from insect stings and who demonstrate hypersensitivity by skin testing with these products. The only approved method for diagnosing insect sting allergic patients for immunization is by skin testing.

This product must never be injected intravenously.

Refer also to CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and OVERDOSAGE for further discussion.

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DESCRIPTION

Hymenoptera Venom Products available are sterile freeze-dried venom of Feromiel (Honey) Bee (Apis mellifera) and venom protein of Yellow Jacket (Vespula sp.), Yellow Hornet (Dolichovespula arenaria), White-Faced Hornet (Dolichovespula maculata) and Wasp (Polistes sp.). Mixed Vespid venom protein (Yellow Jacket, Yellow Hornet and White-Faced Hornet) is also available.

The reconstituted single venom products are intended for subcutaneous injection for immunotherapy and percutaneous use for diagnosis. The Mixed Vespid venom protein is for immunotherapy only, not for diagnosis. Diagnosis should be based on individual venoms.

Because of the difficulty in collecting all species of Yellow Jacket and Wasp, the venom raw materials for these two insects may vary in species composition from lot to lot. A listing of the exact species content for any particular lot of Yellow Jacket or Wasp venom protein may be obtained by calling Technical Services at Jubilant HollisterStier, (800) 992-1120.

Final containers of sterile freeze-dried venom products are sealed under vacuum. This will result in the diluting fluid being forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. See PRECAUTIONS.

Venom or venom protein is supplied in 2 mL diagnostic vials and in 2 mL vials for treatment maintenance. The chart below lists for each vial size the content of lyophilized venom or venom protein and reconstituted product, (mannitol and venom concentrations). Trace amounts of sodium chloride, potassium chloride, acetic acid and beta-alanine, as well as the constituents of the reconstituting fluid, will also be present.


Vial Size µg Venom or

Venom Protein

Reconstitution mg/mL Mannitol Venom Concentration
Single Venom

2 mL

120

1.2 mL

7.7 mg/mL

100µg/mL
Mixed Vespid

2 mL

360

1.2 mL

23.1 mg/mL

300 µg/mL
See product configuration in DOSAGE AND ADMINISTRATION Section.

Maintenance sterile freeze-dried products can be reconstituted in Sterile Albumin Saline with Phenol (which contains 0.9% NaCl, 0.4% phenol and 0.03% Human Serum Albumin) to a concentration of 100 µg/mL (300 µg/mL for Mixed Vespid venom protein). The diagnostic product should be reconstituted only with Sterile Albumin Saline with Phenol (0.4%). See DOSAGE AND ADMINISTRATION for details of dilutions for diagnosis and treatment.

Space is provided on the container label to record the date (month, day, year) venom is reconstituted. Refer to dating period shown under PRECAUTIONS. At the time of reconstitution, write the calculated reconstituted product expiration date (month, day, year) on the vial label in the space provided.

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CLINICAL PHARMACOLOGY

Diagnosis

Diluted solutions of stinging insect venom injected intradermally will produce wheal and erythema reactions in patients who have significant IgE-mediated, Type I immediate hypersensitivity to stings of these insects.

Treatment

Repeated injections of increasing doses of insect venom extracts have been shown to ameliorate the intensity of allergic symptoms upon subsequent insect stings.(3, 4)

The mechanism by which hyposensitization is achieved is not known completely. IgG antibodies (blocking antibodies) appear in the serum of patients treated with injected venom. No direct relationship has been identified between the level of blocking antibody (or the ratio of blocking antibody to IgE antibody directed to the same venom antigens) and the degree of hyposensitization. However, patients who show protection from symptoms after stings have been found to have significant levels of specific blocking antibody.(3, 4)

Initially, after a period of immunotherapy with specific venom antigens, levels of IgE antibody may increase.(4)However, from studies carried out with other venom preparations, these levels are reported to decline after a time.(5) After maintenance level has been reached and maintained, symptoms after stings have been shown to decrease considerably.(3, 4)

It is not known if skin-sensitizing antibody can be eradicated or if the patient can be entirely cured, nor is it known how long immunotherapy must be continued.

In a clinical study with Jubilant HollisterStier venom products, injections (using the Suggested Dose Schedule under DOSAGE AND ADMINISTRATION) were given once per week at one study center, and twice or more per week at another center.(4) (For further discussion, see below). It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom.

In the clinical trial, 97% of patients at the maintenance dosage (100 µg per venom) showed no systemic reaction following an insect sting challenge.(4)The remaining 3% had a milder reaction than noted prior to treatment. The patients in this study reached maintenance (100 µg per venom) usually within 2 1/2 -3 1/2 months after beginning therapy.(4)Whether efficacy of therapy is influenced by the time required to reach maintenance has not yet been determined.

Large local reactions occurred in approximately 60% of the patients given immunotherapy. Some form of systemic response occurred, often repeatedly, in one-third of the patients treated in the clinical trial.(4)Only one systemic response occurred on the first dose given. The rest occurred at various times in the course of immunotherapy. Some systemic manifestations may have occurred because of the patient's apprehension, and did not require treatment. Approximately one-fourth of the patients experiencing systemic responses were given some form of specific therapy (epinephrine, theophylline, or metaproteranol), some on several occasions.(4)

In deciding the criteria for proceeding from dose to dose of the Suggested Dose Schedule, the results of the clinical study (4)should be considered. A study center "A" reporting the least number of systemic reactions during pre-maintenance treatment held the dose constant in most of the cases where significant local reactions occurred. With the systemic reactions reported, this center held the dose the same in approximately 80% of the incidences. The treatment injections were given at this center usually once per week, and if a patient missed an appointment, the next dose was often the same as the preceding dose (depending on the previous reactivity of the patient). Patients treated at this center reached maintenance in an average of 17-19 visits. Another study center "B", reporting a higher incidence of systemic reactions, was more regimented in following the Suggested Dose Schedule. This center reduced or held the dose the same in less than 10% of the cases reporting significant local reactions. With the systemic reactions reported, this center held the dose the same or reduced the dosage in approximately 20% of the cases. At this center, more than one injection per week was given at the outset as circumstances and sensitivity allowed. Patients treated at this center reached maintenance in an average of 14 visits.

Following the achievement of maintenance level (100 µg per venom), approximately 80% or more patients were given a second maintenance injection at a 1-week interval. The third maintenance injection was usually (in approximately 60% of the patients) at a 2-week interval. The next injection was usually within 3 weeks, and thereafter, the patients were injected for ongoing maintenance at approximately monthly intervals.(4)

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INDICATIONS AND USAGE

Insect stings may induce a wide range of allergic symptoms in sensitive patients. A normal sting response is initial burning or stinging pain that may be intense and last several minutes to an hour or more. There is usually some local swelling coming on immediately and persisting for several days. The location of the sting has considerable influence on the intensity of the pain and extent of swelling. Stings on the fingers or feet produce much pain, but less swelling; whereas a sting on the head or face produces extensive swelling with variable pain.

Local reactions coming on rapidly and larger than the usual local reaction, particularly if the swelling spans both adjacent joints on the extremities, can indicate hypersensitivity. Systemic symptoms come on shortly after the sting, often within seconds to minutes. Symptoms may range from generalized flushing, itching, redness, diffuse swelling of the skin or urticarial wheals, abdominal cramps, nausea, vomiting, or incontinence of urine or stool, to faintness, blurring or loss of vision, unconsciousness, seizures, respiratory or cardiac arrest, or death. Later reactions may consist of fever, achiness, malaise, joint swelling, urticaria or other signs of vascular damage typical of serum sickness, a Type III reaction. Typical delayed Type IV reactions may also occur.(6) Rarely, other types of severe reactions to insect stings have been reported.(6)These include serum sickness, hematologic abnormalities, and neurological disorders commencing some time after a sting, and not associated with anaphylactoid reactions. These patients are not candidates for immunotherapy using insect venoms.

(1) Diagnosis

Skin testing with insect venoms is useful to demonstrate the presence of IgE antibodies which account for the patient's symptoms.(3)Patients are seldom able to identify the insect which stung them, so skin testing is used to determine the insect culprit. Dilutions of these venom products will help judge the sensitivity of the patient and whether the patient should be treated.(7)

It is not absolutely known what levels (micrograms) of venom, that elicit positive skin tests, are diagnostic of clinical sensitivity. However, patients with a history of reactions (any of three types: generalized urticaria or angioedema; respiratory difficulty due either to laryngeal edema or to bronchospasm; or vascular collapse, with or without loss of consciousness) to previous stings and a positive skin test to a venom intradermal injection of approximately 1 µg/mL had about a 60% chance of reacting again when stung by the same insect. These patients should receive venom immunotherapy.(3)

Patients with a history of reaction (any of the three reaction types described above) to previous stings, but who did not demonstrate a positive skin test reaction to venom, were considered in a previous study not to be clinically sensitive, and were not treated.(3) We cannot recommend treatment for such patients.

Another study demonstrated false positive reactions when skin testing with venom concentrations of 10 µg/mL and 100 µg/mL was carried out.(8) Thus there can be a nonspecific skin test reaction potentially due to the pharmacological action of the venom at higher concentrations.

The best statement that can be made, at present, is that patients with significant positive history (reactions of the three types described above) following an insect sting, and who do react with a positive skin test to a venom concentration of 1 µg/mL or less, are recommended for treatment. Patients who have the history described above, but who do not react to a 1 µg/mL intradermal venom skin test, cannot be recommended for treatment. At present, the data does not exist, to determine whether a patient who might react to a higher concentration, e.g., 2-10 µg/mL, is at risk from a subsequent sting or not. Since it is not known if sting-sensitive patients who subsequently lose their IgE anti-venom antibody can be resensitized by further stings, it is advisable to retest these patients after any subsequent stings.(3) However, since the level of venom-specific IgE may fall to low levels briefly after a sting, patients should not be re-tested until 2 to 4 weeks after any sting.

(2) Treatment

Immunotherapy is indicated for those patients diagnosed as sensitive and is accomplished by using graduated dilutions of the appropriate insect venom or venoms to control the severity of the patient's symptoms from subsequent stings.

Increasing doses of venom are given at intervals, dependent on the patient's ability to tolerate the venoms, until a maintenance dosage (100 µg per venom is recommended - 300 µg in the case of the Mixed Vespid venom protein) is reached and maintained.

Venom sensitivity differs for individual patients, thus it is not possible to provide a dosage schedule that is universally suited to all patients. The dosage schedule shown under DOSAGE AND ADMINISTRATION is a summary of the schedule used in clinical trials of our product and found suitable for the majority of patients.

In highly sensitive patients, the physician may be required to use a modified dose schedule, based on the patient's sensitivity to and tolerance of the injections. Lower initial doses and smaller dosage increments than shown under DOSAGE AND ADMINISTRATION may be necessary.

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CONTRAINDICATIONS

There are no known absolute contraindications to immunotherapy using Hymenoptera Venom Products. See also PRECAUTIONS and WARNINGS.

Patients showing negative intradermal skin tests to specific venoms at 1 µg/mL are not recommended for venom treatment.

Any injections, including immunotherapy, should be avoided in patients with a bleeding tendency. Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.(1)

Patients on beta blockers may be more reactive to allergens given for testing or treatment and maybe unresponsive to the usual doses of epinephrine used to treat systemic reactions.(2)

Since there are differences of opinion concerning the possibility of routine immunizations exacerbating autoimmune diseases, immunotherapy should be given cautiously to patients with other immunologic diseases and only if the risk from insect stings is greater than the risk of exacerbating the underlying disorder.

WARNINGS

See WARNINGS box at the beginning of this Instruction Sheet. See also PRECAUTIONS.

Venom extract must be temporarily withheld from patients or the dose adjusted downward if any of the following conditions exist: (1) severe symptoms of rhinitis and/or asthma; (2) infection or flu accompanied by fever; (3) any evidence of an excessively large local or any generalized reaction during the initial stages of immunotherapy, or during maintenance therapy; and/or (4) insect sting prior to a scheduled injection. Do not administer venom injections during a period of symptoms following an insect sting or on the day the patient received an insect sting, since this could result in an allergen load that exceeds the patient's tolerance.

THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. DILUTE CONCENTRATED EXTRACTS WITH STERILE ALBUMIN SALINE WITH PHENOL (0.4%) FOR SKIN TESTING AND IMMUNOTHERAPY.

INJECTIONS MUST NEVER BE GIVEN INTRA VENOUSLY. Subcutaneous injection is recommended. Intracutaneous or intramuscular injections may produce large local reactions or be excessively painful. AFTER INSERTING NEEDLE SUBCUTANEOUSLY, BUT BEFORE INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE.

Patients with hypersensitivity to insect venom who undergo desensitization treatment while under concomitant therapy with ACE (angiotensin-converting enzyme) inhibitors, may have an increased risk of life-threatening anaphylactic reactions.(9) Patients without insect venom hypersensitivity, who take ACE inhibitors, and are stung by insects such as bee or wasp can show such reactions as well.(10)

Two patients undergoing desensitization treatment with Hymenoptera Venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.(11) IF CHANGING TO A DIFFERENT LOT OR A FRESHLY RECONSTITUTED VIAL OF VENOM EXTRACT:

All extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. The first dose from the new vial should not exceed 50% of the previous dose.

IF THE VENOM EXTRACT PREVIOUSLY USED WAS FROM ANOTHER MANUFACTURER: Since manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be insured. The starting dose of the venom extract therefore should be greatly decreased even though the extract is the same formula and dilution. In general, a dose reduction to 50% of the previous product dose should be adequate, but each situation must be evaluated separately considering the patient's history of sensitivity, tolerance of previous injections, and other factors. If the patient tolerates a 50% decrease, the next dose could be raised to the previous dose amount. If the decrease is greater than 50%, the next dose would need to be determined by the allergist, depending on the situation. Dose intervals should not exceed one week when rebuilding dose. See DOSAGE AND ADMINISTRATION.

IF A PROLONGED PERIOD OF TIME HAS ELAPSED SINCE THE LAST INJECTION: Patients may lose tolerance for allergen injections during prolonged periods between doses. The duration of tolerance is an individual characteristic and varies from patient to patient. In general, the longer the lapse in the injection schedule, the greater dose reduction required. If the interval since last dose is over four weeks, perform skin tests to determine starting dose. See DOSAGE AND ADMINISTRATION.

IF THE PREVIOUS EXTRACT WAS OUTDATED: The dating period for allergenic extracts indicates the time that they can be expected to remain potent under refrigerated storage conditions (2° - 8°C). During the storage of extracts, even under ideal conditions, some loss of potency occurs. For this reason, extracts should not be used beyond their expiration date. If a patient has been receiving injections of an outdated extract, s/he may experience excessive local or systemic reactions when changed to a new, and possibly more potent extract. In general, the longer the material has been outdated, the greater the dose reduction necessary when starting the fresh extract. Proper selection of the dose and careful injection should prevent most systemic reactions. It must be remembered, however, that allergenic extracts are highly potent in sensitive individuals and that systemic reactions of varying degrees of severity may occur, ranging from mild to life-threatening anaphylaxis, or even death, as described under INDICATIONS AND USAGE and ADVERSE REACTIONS. Patients should be informed of this, and the warnings and precautions should be discussed prior to immunotherapy. See PRECAUTIONS below. Systemic reactions should be treated as indicated in ADVERSE REACTIONS.

PRECAUTIONS

1. GENERAL

The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection.

Concentrated extracts must not be injected unless tolerance has been established.

Diluting fluid should be forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. Failure of this to occur for a particular vial indicates possible loss of vacuum. Vials without vacuum should be returned to the manufacturer.

Record date of reconstitution and expiration date of reconstituted product in the space provided on the product label. Date of expiration after reconstitution must not exceed the Final Expiration Date indicated on the container label..

Store freeze-dried and reconstituted venom product, stock solutions and venom dilutions constantly at 2 - 8 C.

Venom Concentration

Diluent

Recommended Expiration Date*
100 µg/mL

Albumin Saline with Phenol (0.4%)

6 Months

10µg/mL

Albumin Saline with Phenol (0.4%)

1 month

1 µg/mL

Albumin Saline with Phenol (0.4%)

1 month

0.1 µg/mL

Albumin Saline with Phenol (0.4%)

14 days

Less than 0.1 µg/mL

Albumin Saline with Phenol (0.4%)

Prepare fresh daily


*But not to exceed Final Expiration Date indicated on the container label.

Sterile solutions, vials, syringes, etc., should be used and aseptic precautions observed in making dilutions.

To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.

A sterile tuberculin syringe, with a needle at least 5/8" long and graduated in 0.01 mL units, should be used to measure carefully each dose from the appropriate dilution. Aseptic techniques should always be employed when injections are being administered.

A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Patient reactions to previous injections should be reviewed before each new injection so that dose can be adjusted accordingly. See ADVERSE REACTIONS and WARNINGS.

Rarely, a patient is encountered who develops systemic reactions to minute doses of allergen and does not demonstrate increasing tolerance to injections after several months of treatment. It is suggested that if systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped.

PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER SKIN TESTING AND AFTER EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for such treatment measures.

2. INFORMATION FOR PATIENTS

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock.. Patients should be made to understand the importance of a 30 minute observation period following skin testing or therapeutic injections, and be cautioned to return to the office promptly if symptoms occur after leaving. Patients should be instructed in the use of, and have available, an Emergency Anaphylaxis Kit for self-administration of epinephrine.

Patients must be instructed to report any insect stings that have occurred, since a venom injection should not be given on the same day as the sting, nor during a time when the patient is still experiencing symptoms from the sting.

3. DRUG INTERACTIONS

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic, unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.

Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

See WARNINGS section regarding concurrent treatment with ACE inhibitors.

Certain medications may lessen the skin test wheal and erythema responses elicited by allergens and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihistamines should be discontinued for at least 3 weeks prior to skin testing.(17) Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.(17, 18)

Tricyclic antidepressants such as doxepin, should be withheld for at least 7 days before skin testing.(19) Topical local anesthetics may suppress the flare responses and should be avoided on skin test sites.(20)

When using other drugs in patients receiving allergenic extracts, always consult the product labeling of the other drugs to determine any possible interaction with use of allergenic extracts, and specifically with stinging insect (Hymenoptera) venom extracts.

4. CARCINOGENESIS AND MUTAGENSIS AND IMPAIRMENT OF FERTILITY

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity, or impairment of fertility.

5. PREGNANCY

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

On the basis of histamine's known ability to contract uterine muscle, theoretically, a systemic reaction, whether occurring from insect sting or from venom skin testing or treatment dose, should be avoided. Therefore, the physician must carefully consider the benefit-to-risk ratio, to both patient and fetus, of continuing venom immunotherapy during pregnancy, or performing venom skin testing, and especially of initiating a venom immunotherapy program where there is a possibility that the patient may not be able to reach the recommended maintenance dose without significant risk of a systemic reaction.

6. NURSING MOTHERS

There are no current studies on secretion of the allergenic extract components in human milk or effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

7. PEDIATRIC USE

Since dosage for the pediatric population is the same as for adults, the larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit. A study done in children ages 4 to 17 showed no special problems with venom immunotherapy in this population.

8. GERIATRIC USE

The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease.(23)

ADVERSE REACTIONS

Physicians administering Hymenoptera Venom testing or treatment materials should be experienced in the treatment of severe systemic reactions.

(1) Local Reactions

Some erythema, swelling or pruritis at the site of injection are common, the extent varying with the patient. Excessively large, painful or persistent local reactions can occur from skin tests or immunotherapy. Frequent application of cold, wet dressings to the area and/or the use of oral antihistamines will ameliorate the discomfort. Reactions usually subside in 24-36 hours. Large local reactions occurred in approximately 60% of the patients given immunotherapy in a clinical study. None of the local reactions required specific treatment; however, subsequent injections in many instances were held to the previous dose or a reduced dose. Some patients had repeated large local reactions that slowed the increase in the immunotherapy dose.4

See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION Sections.

A mild burning immediately after the injection is to be expected. This usually leaves in 10 to 20 seconds. See also WARNINGS and PRECAUTIONS regarding proper method and route of injection.

(2) Systemic Reactions

Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life threatening from anaphylaxis as described under INDICATIONS AND USAGE.

With careful attention to dosage and administration, severe systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals, any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions. See CLINICAL PHARMACOLOGY for clinical incidence of systemic reactions and course of action following these reactions.

If a systemic or anaphylactic reaction does occur, inject 1:1000 epinephrine-hydrochloride intramuscularly or subcutaneously.

EPINEPHRINE DOSAGE

ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.

PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient.

After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patency should be insured. Oxygen should be given by mask. Intravenous antihistamines, inhaled bronchodilators, theophylline and/or corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given.

Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures [Ref. J. Allergy and Clinical Immunology, 77(2): p.271-273, 1986]. Rarely are all of the above measures necessary; epinephrine usually produces a prompt response. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance. For recommendations regarding how to proceed with venom extract dose following systemic reactions, see WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION.

3. Adverse Event Reporting

Report all adverse events to Jubilant HollisterStier LLC Customer Technical Services Department at 1(800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1(800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1(800) FDA-0178.

OVERDOSAGE

See ADVERSE REACTIONS Section.

DOSAGE AND ADMINISTRATION

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment.

Reconstitute the freeze-dried venoms by adding 1.2 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming.

Dilutions must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Maintain stock solutions and dilutions constantly at 2° - 8°C.

Extract of Volume Extract Concentration

Diluent Volume

Dilution Concentration
1 part of

100 µg/mL

+

9 parts

=

10 µg/mL

1 part of

10 µg/mL

+

9 parts

=

1 µg/mL

1 part of

1µg/mL

+

9 parts

=

0.1µg/mL

1 part of

0.1 µg/mL

+

9 parts

=

0.01 µg/mL

1 part of

0.01 µg/mL

+

9 parts

=

0.001 µg/mL

1 part of

0.001 µg/mL

+

9 parts

=

0.0001 µg/mL

As an example of the above dilution table:

Extract of Volume Extract Concentration

Diluent Volume

Dilution Concentration
0.2mL of

100 µg/mL

+

1.8mL

=

10 µg/mL

0.2mL of

10 µg/mL

+

1.8mL

=

1 µg/mL

0.2mL of

1 µg/mL

+

1.8mL

=

0.1 µg/mL

0.2mL of

0.1 µg/mL

+

1.8mL

=

0.01 µg/mL

0.2mL of

0.01 µg/mL

+

1.8mL

=

0.001 µg/mL

0.2mL of

0.001 µg/mL

+

1.8mL

=

0.0001 µg/mL

NOTE: Mixed Vespid Venom Protein concentrations will be three times that shown above.

USE OF VENOMIL DIAGNOSTIC SETS

The Venomil Diagnostic Sets from Jubilant HollisterStier contain a vial of freeze dried venom protein that when reconstituted as instructed below will contain 100 µg venom or venom protein/mL.

To use the Venomil Diagnostic set, follow these steps:

1. Open box and remove contents. Be sure to read the complete package Instruction Sheet paying particular attention to the WARNINGS, PRECAUTIONS, CONTRAINDICATIONS, and ADVERSE REACTIONS.

2. Remove the freeze-dried venom vial and one of the seven vials of diluent from the kit. Withdraw 1.3 mL of Albumin Saline with Phenol (0.4%) from the diluent vial using a 2 or 3 mL disposable syringe. Expel some Albumin Saline with Phenol (0.4%) from the syringe until exactly 1.2 mL are remaining in the syringe. The remaining Albumin Saline with Phenol (0.4%) in the diluent vial may be marked "Control" and used as a negative control for prick testing.

3. Insert the needle of the diluent syringe into the vial of venom and expel the diluent. Remove the syringe. Swirl or rock the vial to dissolve the venom completely. DO NOT SHAKE. Shaking can cause foaming of the extract.

At this point, you have completed the reconstitution of the freeze-dried venom. The reconstituted products contain 100 µg of venom or venom protein per mL. DO NOT USE THIS STRENGTH FOR INTRADERMAL SKIN TESTING. DISCARD AFTER THE DILUTIONS HAVE BEEN PREPARED.

4. Remove six vial labels from the kit and mark them: 10 µg/mL, 1 µg/mL, 0.1 µg/mL, 0.01 µg/mL, 0.001 µg/mL and 0.0001 µg/mL. Withdraw 0.2 mL of venom extract in a 1 mL syringe from the vial reconstituted in step #3. Insert the syringe needle into one vial of 1.8 mL Albumin Saline with Phenol (0.4%). Slowly expel the 0.2 mL venom into it. Swirl or rock to mix, and label 10 µg/mL.

5. Withdraw 0.2 mL of the 10 µg/mL venom extract and inject into another vial of 1.8 mL Albumin Saline with Phenol (0.4%). Mix and label 1 µg/mL.

6. The four additional dilutions should be prepared in the same manner.

(2) Diagnosis

Since the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting. Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities.(4) Mixed Vespid venom protein should be used only for therapy - not for diagnosis.

Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule. See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION.

In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is also recommended.

The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient.

Prick Tests: Prick tests are accomplished by applying one drop of the 1 µg/mL venom extract to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood.

Skin response should be assessed after approximately 15-20 minutes.

For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom.

Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL.

A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb.

Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until a concentration of 1 µg/mL has been tested, whichever occurs first.

A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less,(8)providing that this reaction is greater than that of the diluent control.

(3) Immunotherapy

For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

The most common site of injection is the lateral aspect of the upper arm.

Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions.

CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in

clinical trials(4)and should be suitable for a majority of patients.

IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient's sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom).

In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive.

Suggested Dose Schedule for a Single Venom:

Dose No. *Volume of 1 µg/mL Dose No. Volume of 10 µg/mL Dose No. Volume of 100 µg/mL
1..... ...0.05 mL 5..... ...0.05 mL 9..... ...0.05mL
2..... ...0.10 mL 6..... ...0.10 mL 10.... ...0.10mL
3..... ...0.20 mL 7..... ...0.20 mL 11.... ...0.20mL
4..... ...0.40 mL 8..... ...0.40 mL 12.... ...0.40mL
13.... ...0.60mL
14.... ...0.80mL
15.... ...1.00mL

Mixed Vespid Venom will contain three times the venom protein per mL shown in this table.

*See preceding CAUTION Section.

ALTERNATE MAINTENANCE DOSE SCHEDULE

If the above suggested dosage schedule has been followed, Dose #15 will have emptied the third vial of venom. There should now be three vials of freeze-dried venom remaining in the maintenance set. If a smaller volume maintenance dose is desired, then the remaining vials of venom may be reconstituted with 0.6 mL of Sterile Albumin Saline with Phenol (0.4%) instead of the previously recommended 1.2 mL. When 0.6 mL is used for reconstitution, the maintenance dose volume then becomes 0.5 mL instead of 1.0 mL. The 0.5 mL injection will still contain 100 micrograms of venom or venom protein.

Precautions should be taken to ensure that maintenance level injections of 0.5 mL are given only from those vials of venom that have been reconstituted with 0.6 mL of diluting fluid. Any other volume used for reconstitution will not give 100 micrograms of venom or venom protein at a dosage of 0.5 mL In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients) it is recommended that injections be given at least once per week, as in the clinical studies.. When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patient's tolerance of the extract.

Based on the clinical studies (4)it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center "A," which reported the least number of systemic reactions during the course of therapy.

It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance.

See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based.

The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.

PEDIATRIC USE

The dose for the pediatric population is the same as for adults..

GERIATRIC USE

The dose for elderly patients is the same as for adult patients under 65.(23).

HOW SUPPLIED

Jubilant HollisterStier LLC sterile freeze-dried Hymenoptera Venom Products are supplied in vacuum-sealed vials containing venom extract with mannitol as an excipient.. Reconstituting fluid [Sterile Albumin Saline with Phenol (0.4%)] is supplied with the Venomil® kit, and is also available separately.


Storage:

Store freeze-dried and reconstituted venom product, and venom dilutions, at 2° - 8° C, and keep at this temperature range during office use.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.

No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Lockey, Richard F., Linda M. Benedict, Paul C. Turkeltaub, Samuel C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79 (4): 660-677, 1987.

2. Jacobs, Robert L., Goeffrey W. Rake, Jr., et. al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol. 68 (2): 125-127, August 1981.

3. Hunt, K. J., M. D. Valentine, A. K. Sobotka, A. W. Benton, F. J. Amodio, L. M. Lichtenstein. A controlled trial of immunotherapy in insect hypersensitivity. New Eng. J. Med. 299: 157-161, July 27, 1978.

4. Summary of data from BB-IND 1292 clinical studies, 1978-79, on Hollister-Stier products.

5. Amodio, F., L. Markley, M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Maintenance immunotherapy for Hymenoptera sensitivity. J. Allergy Clin. Immunol. 61 (3): 134, 1978.

6. Reisman, R. E., Allergy Principles and Practice. E. Middleton, C. E. Reed, E. F. Ellis, ed. C. V. Mosby Co., 1978.

7. Sobotka, A. K., N. F. Adkinson, Jr., M. D. Valentine, L. M. Lichtenstein. Allergy to insect stings. IV. Diagnosis by R.A.S.T. J. Immunol. 121 (6): 2477-2484, 1978.

8. Hunt, K. J., M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Annals Int. Med. 85: 56-59, 1976.

9. Annals of Allergy, Asthma and Immunology. Inhibitors of angiotensin II: Potential hazards for patients at risk for anaphylaxis. Editorial. 78: 527-529, June 1997.

10. Pharm. Ind. (Germany). Anaphylactoid reactions in patients treated with ACE inhibitor treatment in combination with desensitization treatment or after insect bites. 56 (9): IX226-227, 1994.

11. Tunon-De-Lara, J. M., et al. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. The Lancet (United Kingdom). 340 (8824): 908, Oct. 10, 1992.

12. Weinstien, A. M., B. D. Dubin, W. K. Podleski, S. L. Spector, R. S. Farr. Asthma and pregnancy. JAMA. 124 (11): 1161-1165, 1979.

13. Reid, M. J., R. F. Lockey, P. C. Turkletaub, T. A. E. Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. Allergy Clin. Immunol. 92 (1): 6-15, July 1993.

14. Reid, M. J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97 (1) Part 3:231, Abstract 195, January 1996.

15. Thompson, R. A. et al. Report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989.

16. Malling, H.J., B. Weeke, et al. The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993.

17. Pipkorn, Ulf. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86, 1988.

18. Andersson, M. U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.

19. Rao, Kamineni S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.

20. Pipkorn, Ulf, M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987.

21. DuBuske, L. M., C. J. Ling, A. L. Sheffer. Special problems regarding allergy immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12 (1): 145-175, 1992.

22. Graft, D., K. Schuberth, A. Kagey-Sobotka, K. Kwiterovich, Y. Niv, L. Lichtenstein, M. Valentine. Assessment of prolonged venom immunotherapy in children. J. Allergy Clin. Immunol. 80 (2): 162-169, August 1987.

23. Peebles, Ray Stokes, Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunol. Allergy Clin. of North Am. 13 (3): 627-646, August 1993.

Suggested Dosage Table

Iron (Ferrous Pidolate):


1 INDICATIONS AND USAGE

Feromiel (Iron (Ferrous Pidolate)) is indicated for the treatment of Feromiel (Iron (Ferrous Pidolate)) deficiency anemia in patients with chronic kidney disease (CKD).

Feromiel (Iron (Ferrous Pidolate)) is an Feromiel (Iron (Ferrous Pidolate)) replacement product indicated for the treatment of Feromiel (Iron (Ferrous Pidolate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Feromiel ) must only be administered intravenously either by slow injection or by infusion. The dosage of Feromiel (Iron (Ferrous Pidolate)) is expressed in mg of elemental Feromiel (Iron (Ferrous Pidolate)). Each mL contains 20 mg of elemental Feromiel (Iron (Ferrous Pidolate)).

Population Dose
Adult patients Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD) (2.1) 100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2) 200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3) 300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5) 0.5 mg/kg slow intravenous injection or infusion

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Feromiel (Iron (Ferrous Pidolate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Feromiel (Iron (Ferrous Pidolate)) should be administered early during the dialysis session. The usual total treatment course of Feromiel (Iron (Ferrous Pidolate)) is 1000 mg. Feromiel (Iron (Ferrous Pidolate)) treatment may be repeated if Feromiel (Iron (Ferrous Pidolate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Feromiel (Iron (Ferrous Pidolate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Feromiel (Iron (Ferrous Pidolate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Feromiel (Iron (Ferrous Pidolate)) treatment may be repeated if Feromiel (Iron (Ferrous Pidolate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Feromiel (Iron (Ferrous Pidolate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Feromiel (Iron (Ferrous Pidolate)) in a maximum of 250 mL of 0.9% NaCl. Feromiel (Iron (Ferrous Pidolate)) treatment may be repeated if Feromiel (Iron (Ferrous Pidolate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Feromiel (Iron (Ferrous Pidolate)) maintenance treatment

The dosing for Feromiel (Iron (Ferrous Pidolate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Feromiel (Iron (Ferrous Pidolate)) maintenance treatment: Administer Feromiel (Iron (Ferrous Pidolate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Feromiel (Iron (Ferrous Pidolate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Feromiel (Iron (Ferrous Pidolate)) maintenance treatment

The dosing for Feromiel (Iron (Ferrous Pidolate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Feromiel (Iron (Ferrous Pidolate)) maintenance treatment: Administer Feromiel (Iron (Ferrous Pidolate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Feromiel (Iron (Ferrous Pidolate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

  • 10 mL single-use vial / 200 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL)
  • 5 mL single-use vial / 100 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL)
  • 2.5 mL single-use vial / 50 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL)
  • 10 mL single-use vial / 200 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL) (3)
  • 5 mL single-use vial / 100 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL) (3)
  • 2.5 mL single-use vial / 50 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

  • Known hypersensitivity to Feromiel (Iron (Ferrous Pidolate))
  • Known hypersensitivity to Feromiel (Iron (Ferrous Pidolate)) (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Feromiel ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Feromiel (Iron (Ferrous Pidolate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
  • Hypotension: Feromiel (Iron (Ferrous Pidolate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Feromiel (Iron (Ferrous Pidolate)). (5.2)
  • Feromiel (Iron (Ferrous Pidolate)) Overload: Regularly monitor hematologic responses during Feromiel (Iron (Ferrous Pidolate)) therapy. Do not administer Feromiel (Iron (Ferrous Pidolate)) to patients with Feromiel (Iron (Ferrous Pidolate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Feromiel (Iron (Ferrous Pidolate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Feromiel (Iron (Ferrous Pidolate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Feromiel (Iron (Ferrous Pidolate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Feromiel (Iron (Ferrous Pidolate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Feromiel (Iron (Ferrous Pidolate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Feromiel ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Feromiel (Iron (Ferrous Pidolate)). Hypotension following administration of Feromiel (Iron (Ferrous Pidolate)) may be related to the rate of administration and/or total dose administered .

5.3 Feromiel (Iron (Ferrous Pidolate)) Overload

Excessive therapy with parenteral Feromiel (Iron (Ferrous Pidolate)) can lead to excess storage of Feromiel (Iron (Ferrous Pidolate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Feromiel (Iron (Ferrous Pidolate)) require periodic monitoring of hematologic and Feromiel (Iron (Ferrous Pidolate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Feromiel (Iron (Ferrous Pidolate)) to patients with evidence of Feromiel (Iron (Ferrous Pidolate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Feromiel (Iron (Ferrous Pidolate)) sucrose; do not perform serum Feromiel (Iron (Ferrous Pidolate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Feromiel ) are described in other sections .

  • The most common adverse reactions (≥2%) following the administration of Feromiel (Iron (Ferrous Pidolate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Feromiel ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Feromiel (Iron (Ferrous Pidolate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.


* EPO=Erythropoietin

Adverse Reactions

(Preferred Term)

HDD-CKD NDD-CKD PDD-CKD
Feromiel (Iron (Ferrous Pidolate)) Feromiel (Iron (Ferrous Pidolate)) Oral Feromiel (Iron (Ferrous Pidolate)) Feromiel (Iron (Ferrous Pidolate)) EPO* Only
(N=231) (N=139) (N=139) (N=75) (N=46)
% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2
Ear and Labyrinth Disorders
Ear Pain 0 2.2 0.7 0 0
Eye Disorders
Conjunctivitis 0.4 0 0 2.7 0
Gastrointestinal Disorders
Abdominal pain 3.5 1.4 2.9 4.0 6.5
Diarrhea 5.2 7.2 10.1 8.0 4.3
Dysgeusia 0.9 7.9 0 0 0
Nausea 14.7 8.6 12.2 5.3 4.3
Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders and
Administration Site Conditions
Asthenia 2.2 0.7 2.2 2.7 0
Chest pain 6.1 1.4 0 2.7 0
Feeling abnormal 3.0 0 0 0 0
Infusion site pain or burning 0 5.8 0 0 0
Injection site extravasation 0 2.2 0 0 0
Peripheral edema 2.6 7.2 5.0 5.3 10.9
Pyrexia 3.0 0.7 0.7 1.3 0
Infections and Infestations
Nasopharyngitis, Sinusitis, Upper

respiratory tract infections, Pharyngitis

2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and Procedural
Complications
Graft complication 9.5 1.4 0 0 0
Metabolism and Nutrition Disorders
Fluid overload 3.0 1.4 0.7 1.3 0
Gout 0 2.9 1.4 0 0
Hyperglycemia 0 2.9 0 0 2.2
Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgia 3.5 1.4 2.2 4.0 4.3
Back pain 2.2 2.2 3.6 1.3 4.3
Muscle cramp 29.4 0.7 0.7 2.7 0
Myalgia 0 3.6 0 1.3 0
Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System Disorders
Dizziness 6.5 6.5 1.4 1.3 4.3
Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic and
Mediastinal Disorders
Cough 3.0 2.2 0.7 1.3 0
Dyspnea 3.5 5.8 1.4 1.3 2.2
Nasal congestion 0 1.4 2.2 1.3 0
Skin and Subcutaneous
Tissue Disorders
Pruritus 3.9 2.2 4.3 2.7 0
Vascular Disorders
Hypertension 6.5 6.5 4.3 8.0 6.5
Hypotension 39.4 2.2 0.7 2.7 2.2

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Feromiel (Iron (Ferrous Pidolate)) therapy and were reported to be intolerant (defined as precluding further use of that Feromiel (Iron (Ferrous Pidolate)) product). When these patients were treated with Feromiel (Iron (Ferrous Pidolate)) there were no occurrences of adverse reactions that precluded further use of Feromiel (Iron (Ferrous Pidolate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Feromiel (Iron (Ferrous Pidolate)) maintenance treatment with Feromiel (Iron (Ferrous Pidolate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Feromiel (Iron (Ferrous Pidolate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Feromiel (Iron (Ferrous Pidolate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Feromiel (Iron (Ferrous Pidolate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Feromiel (Iron (Ferrous Pidolate)) 0.5 mg/kg group, 10 (21%) patients in the Feromiel (Iron (Ferrous Pidolate)) 1.0 mg/kg group, and 10 (21%) patients in the Feromiel (Iron (Ferrous Pidolate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Feromiel (Iron (Ferrous Pidolate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Feromiel (Iron (Ferrous Pidolate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Feromiel (Iron (Ferrous Pidolate)) injection. Reactions have occurred following the first dose or subsequent doses of Feromiel (Iron (Ferrous Pidolate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Feromiel (Iron (Ferrous Pidolate)) have not been studied. However, Feromiel (Iron (Ferrous Pidolate)) may reduce the absorption of concomitantly administered oral Feromiel (Iron (Ferrous Pidolate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Feromiel ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Feromiel (Iron (Ferrous Pidolate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Feromiel (Iron (Ferrous Pidolate)) sucrose. Because animal reproductive studies are not always predictive of human response, Feromiel (Iron (Ferrous Pidolate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Feromiel (Iron (Ferrous Pidolate)) sucrose is excreted in human milk. Feromiel (Iron (Ferrous Pidolate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Feromiel (Iron (Ferrous Pidolate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Feromiel ) for Feromiel (Iron (Ferrous Pidolate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Feromiel (Iron (Ferrous Pidolate)) for Feromiel (Iron (Ferrous Pidolate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Feromiel (Iron (Ferrous Pidolate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Feromiel (Iron (Ferrous Pidolate)) has not been studied in patients younger than 2 years of age.

In a country where Feromiel (Iron (Ferrous Pidolate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Feromiel (Iron (Ferrous Pidolate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Feromiel (Iron (Ferrous Pidolate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Feromiel (Iron (Ferrous Pidolate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Feromiel (Iron (Ferrous Pidolate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Feromiel (Iron (Ferrous Pidolate)) in humans. Excessive dosages of Feromiel (Iron (Ferrous Pidolate)) may lead to accumulation of Feromiel (Iron (Ferrous Pidolate)) in storage sites potentially leading to hemosiderosis. Do not administer Feromiel (Iron (Ferrous Pidolate)) to patients with Feromiel (Iron (Ferrous Pidolate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Feromiel (Iron (Ferrous Pidolate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Feromiel (Iron (Ferrous Pidolate)) (iron sucrose injection, USP), an Feromiel (Iron (Ferrous Pidolate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Feromiel (Iron (Ferrous Pidolate)) (III)-hydroxide in sucrose for intravenous use. Feromiel (Iron (Ferrous Pidolate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na2Fe5O8(OH) ·3(H2O)]n ·m(C12H22O11)

where: n is the degree of Feromiel (Iron (Ferrous Pidolate)) polymerization and m is the number of sucrose molecules associated with the Feromiel (Iron (Ferrous Pidolate)) (III)-hydroxide.

Each mL contains 20 mg elemental Feromiel (Iron (Ferrous Pidolate)) as Feromiel (Iron (Ferrous Pidolate)) sucrose in water for injection. Feromiel (Iron (Ferrous Pidolate)) is available in 10 mL single-use vials (200 mg elemental Feromiel (Iron (Ferrous Pidolate)) per 10 mL), 5 mL single-use vials (100 mg elemental Feromiel (Iron (Ferrous Pidolate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Feromiel (Iron (Ferrous Pidolate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Feromiel ) is an aqueous complex of poly-nuclear Feromiel (Iron (Ferrous Pidolate)) (III)-hydroxide in sucrose. Following intravenous administration, Feromiel (Iron (Ferrous Pidolate)) is dissociated into Feromiel (Iron (Ferrous Pidolate)) and sucrose and the Feromiel (Iron (Ferrous Pidolate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Feromiel (Iron (Ferrous Pidolate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Feromiel (Iron (Ferrous Pidolate)) is dissociated into Feromiel (Iron (Ferrous Pidolate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Feromiel (Iron (Ferrous Pidolate)) sucrose containing 100 mg of Feromiel (Iron (Ferrous Pidolate)), three times weekly for three weeks, significant increases in serum Feromiel (Iron (Ferrous Pidolate)) and serum ferritin and significant decreases in total Feromiel (Iron (Ferrous Pidolate)) binding capacity occurred four weeks from the initiation of Feromiel (Iron (Ferrous Pidolate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Feromiel ), its Feromiel (Iron (Ferrous Pidolate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Feromiel (Iron (Ferrous Pidolate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Feromiel (Iron (Ferrous Pidolate)) containing 100 mg of Feromiel (Iron (Ferrous Pidolate)) labeled with 52Fe/59Fe in patients with Feromiel (Iron (Ferrous Pidolate)) deficiency showed that a significant amount of the administered Feromiel (Iron (Ferrous Pidolate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Feromiel (Iron (Ferrous Pidolate)) trapping compartment.

Following intravenous administration of Feromiel (Iron (Ferrous Pidolate)), Feromiel (Iron (Ferrous Pidolate)) sucrose is dissociated into Feromiel (Iron (Ferrous Pidolate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Feromiel (Iron (Ferrous Pidolate)) containing 1,510 mg of sucrose and 100 mg of Feromiel (Iron (Ferrous Pidolate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Feromiel (Iron (Ferrous Pidolate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Feromiel (Iron (Ferrous Pidolate)) sucrose containing 500 to 700 mg of Feromiel (Iron (Ferrous Pidolate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Feromiel (Iron (Ferrous Pidolate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Feromiel (Iron (Ferrous Pidolate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Feromiel (Iron (Ferrous Pidolate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Feromiel (Iron (Ferrous Pidolate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Feromiel (Iron (Ferrous Pidolate)), the half-life of total serum Feromiel (Iron (Ferrous Pidolate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Feromiel (Iron (Ferrous Pidolate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Feromiel (Iron (Ferrous Pidolate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Feromiel (Iron (Ferrous Pidolate)) sucrose.

Feromiel (Iron (Ferrous Pidolate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Feromiel (Iron (Ferrous Pidolate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Feromiel (Iron (Ferrous Pidolate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Feromiel (Iron (Ferrous Pidolate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Feromiel ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Feromiel (Iron (Ferrous Pidolate)) treatment and 24 in the historical control group) with Feromiel (Iron (Ferrous Pidolate)) deficiency anemia. Eligibility criteria for Feromiel (Iron (Ferrous Pidolate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Feromiel (Iron (Ferrous Pidolate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Feromiel (Iron (Ferrous Pidolate)), who were off intravenous Feromiel (Iron (Ferrous Pidolate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Feromiel (Iron (Ferrous Pidolate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.


**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose as covariates.


Efficacy

parameters

End of treatment 2 week follow-up 5 week follow-up
Feromiel (Iron (Ferrous Pidolate)) (n=69 Historical Control (n=18) Feromiel (Iron (Ferrous Pidolate))

(n=73)

Historical Control

(n=18)

Feromiel (Iron (Ferrous Pidolate))

(n=71)

Historical

Control

(n=15)

Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Feromiel (Iron (Ferrous Pidolate)) in 23 patients with Feromiel (Iron (Ferrous Pidolate)) deficiency and HDD-CKD who had been discontinued from Feromiel (Iron (Ferrous Pidolate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Feromiel (Iron (Ferrous Pidolate)). Exclusion criteria were similar to those in studies A and B. Feromiel (Iron (Ferrous Pidolate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Feromiel (Iron (Ferrous Pidolate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Feromiel (Iron (Ferrous Pidolate)) versus Feromiel (Iron (Ferrous Pidolate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Feromiel (Iron (Ferrous Pidolate)) (325 mg ferrous sulfate three times daily for 56 days); or Feromiel (Iron (Ferrous Pidolate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Feromiel (Iron (Ferrous Pidolate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Feromiel (Iron (Ferrous Pidolate)) group.

A statistically significantly greater proportion of Feromiel (Iron (Ferrous Pidolate)) subjects (35/79; 44.3%) compared to oral Feromiel (Iron (Ferrous Pidolate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Feromiel (Iron (Ferrous Pidolate)) to patients with PDD-CKD receiving an erythropoietin alone without Feromiel (Iron (Ferrous Pidolate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Feromiel (Iron (Ferrous Pidolate)) or Feromiel (Iron (Ferrous Pidolate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Feromiel (Iron (Ferrous Pidolate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Feromiel (Iron (Ferrous Pidolate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Feromiel (Iron (Ferrous Pidolate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Feromiel ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Feromiel (Iron (Ferrous Pidolate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Feromiel (Iron (Ferrous Pidolate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Feromiel (Iron (Ferrous Pidolate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Feromiel (Iron (Ferrous Pidolate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Feromiel (Iron (Ferrous Pidolate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Feromiel ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Feromiel (Iron (Ferrous Pidolate)), each 5 mL vial contains 100 mg elemental Feromiel (Iron (Ferrous Pidolate)), and each 2.5 mL vial contains 50 mg elemental Feromiel (Iron (Ferrous Pidolate)) (20 mg/mL).

NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5
NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10
NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually Boxed
NDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25
NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10
NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10
NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 25

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Feromiel (Iron (Ferrous Pidolate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Feromiel (Iron (Ferrous Pidolate)) per mL, or undiluted (20 mg elemental Feromiel (Iron (Ferrous Pidolate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Feromiel (Iron (Ferrous Pidolate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Feromiel (Iron (Ferrous Pidolate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Feromiel (Iron (Ferrous Pidolate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Feromiel (Iron (Ferrous Pidolate)) administration:

  • Question patients regarding any prior history of reactions to parenteral Feromiel (Iron (Ferrous Pidolate)) products
  • Advise patients of the risks associated with Feromiel (Iron (Ferrous Pidolate))
  • Advise patients to report any symptoms of hypersensitivity that may develop during and following Feromiel (Iron (Ferrous Pidolate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Feromiel (Iron (Ferrous Pidolate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx® is a trademark of Premier, Inc., used under license.

PREMIERProRx®

IN2340

MG #15727

Feromiel pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Feromiel available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Feromiel destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Feromiel Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Feromiel pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. "Iron". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  2. "Iron". http://www.drugbank.ca/drugs/DB0159... (accessed August 28, 2018).
  3. "E1UOL152H7: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Feromiel?

Depending on the reaction of the Feromiel after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Feromiel not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Feromiel addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Feromiel, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Feromiel consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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