HEALTH CARE PROVIDER LETTER SECTION.

Dear Healthcare Provider Letter. Laboratoire AGUETTANT Rue Alexander Fleming 69007 LYON FRANCEIMPORTANT DRUG INFORMATIONZINC INJECTION AVAILABILITYJuly 23, 2013Subject: Temporary importation of Zinc injectable mg/ml (zinc gluconate trihydrate) solution for infusion (equivalent to elemental zinc mg/mL)Dear Healthcare Professional,Due to the current critical shortage of zinc injection drug products in the United States (U.S.), Laboratoire Aguettant (Aguettant) is coordinating with the Food and Drug Administration (FDA) to increase the availability of these products. Aguettant has initiated temporary importation into the U.S., through its U.S. distributor Baxter Healthcare Corporation, the non-FDA-approved zinc-containing drug, Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion (equivalent to elemental zinc mg/mL): Lot T-7506C, expiration date 02-2015, and Lot T-7519C, expiration date 03-2015.This product is marketed in France, and is manufactured for Aguettant at FDA-inspected facility in France that is in compliance with Good Manufacturing Practices (GMP) regulations enforced in Europe.At this time, FDAs regulatory discretion for the importation and distribution of Aguettants Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion (equivalent to elemental zinc mg/mL) is limited to Aguettant and its distributor Baxter Healthcare Corporation during the critical shortage of zinc injection. Importation and distributionof this product in the United States byany entity other than Aguettant and its distributor Baxter Healthcare Corporation is outside the scope of FDAs regulatory discretion, and FDA has not approved Aguettants Zinc injectable product in the U.S.Effective immediately, and during this temporary period, Aguettant will offer the following presentation of zinc injection: Zinc Injectable(zinc gluconate trihydrate)1 mg/mL, solution for infusion10 mL glass vialsAuthorization 333 414-4 (France)Box of 10 vialsThe vial and carton labels will display the original French product labels as marketed inFrance. At the end of this letter is product comparison table with the French prescribing information translated into English, as well as images of the French labels with their English translation for your reference.Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion is meant to be used the same way as the U.S. marketed drugs, and provides mg/mL of elemental zinc. Each vial is single use only and must be diluted prior to infusion. Please discard each vial after single use.There are some key differences in labeling between the FDA-approved zinc injection drug product and Aguettants zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion (please see also the product comparison tables attached).Zinc injectable mg/mL solution for infusion (equivalent to elemental zinc mg/mL) contains zinc gluconate trihydrate as the active substance, which is different salt than those used in other zinc drugs for injection, i.e. zinc chloride and zinc sulfate. Also, note that our manufacturer of zinc gluconate trihydrate complies with the U.S. Pharmacopoeia monograph for zinc gluconate trihydrate. We consider this formulation an appropriate alternative to the FDA-approved zinc injection drug product when used as explained below.The composition in active substance is equivalent to one milligram of elemental zinc per milliliter of solution. The only excipient is water for injections, and the pH of the drug is comprised between 5.5 and 7.0.No specific precautions are required for the storage of Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion. As with your usual zinc injection drug products, you may store this at controlled room temperature 20C to 25C (68F to 77F). Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion is available only by prescription in theU.S.Please refer to the package insert for the FDA-approved zinc injection drug product for full prescribing information and follow the instructions presented in the FDA-approved package insert for dosing and use in pregnancy recommendations. Please note the difference in the maximum potential aluminum content (higher in the foreign product).Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion is meant to be used by parenteral administration (infusion), only after dilution in an isotonic solution or in mixture for parenteral nutrition.Dosing instructions for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion differ from dosing instructions for the FDA-approved zinc injection drug product. We recommend that you follow the labeling instructions for the FDA-approved zinc injection drug product.Instructions regarding use in pregnancy for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion differ from dosing instructions for the FDA-approved zinc injection drug product. We recommend that you follow the labeling instructions for the FDA-approved zinc injection drug product.Maximum potential aluminum content for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion is higher than that for the FDA-approved zinc injection drug product. Consider risks of aluminum toxicity against benefit of zinc supplementation when prescribing Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion.The aluminum content of Lot T-7506C and Lot T-7519C is each no more than 100 mcg/L at the time of this import. Aluminum testing is not requirement for registration of this product inFrance. However in support of FDAs regulatory discretion for temporary importation, testing was performed perU.S.regulation 21 CFR 201.323. The aluminum content for lots at expiry was found to be no higher than 350 mcg/L.The barcodemay not registeraccurately on the U.S. scanning systems. Institutions should manually input the product into their systems and confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients. To place an order, or if you have any questions about the information contained in this letter or the use of Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion, please call Baxters Center for Service at 1-888-229-0001, available from 7:00 am to 6:00 pm Central Standard Time, or email CFSCustomerServicebaxter.com.We encourage health care providers to report any adverse events and medication errors that occur while using this product, as for any other drug. To report adverse events associated with Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion, please call Baxter Healthcare Surveillance at 1-866-888-2472 (Monday Friday 9:00 am to 5:00 pm Central Standard Time), or fax at 1-800-759-1801 (24 hrs/day, days/week).Adverse events that may be related to the use of this product may also be reported to FDAs MedWatch Adverse Event Reporting Program either online, by regular mail or by fax:Online: http://www.fda.gov/medwatch/report.htmRegular mail: Use postage paid FDA form 3500 available at :http://www.fda.gov/medwatch/getforms.htmMail to MedWatch FDA,5600 Fishers Lane,Rockville,MD20852-9787Fax: 1-800-FDA-0178We remain at your disposal to answer the questions you might have about our product, and provide more information if needed.Thank you for your understanding,Eric ROUGEMOND, MD CEO of Laboratoire AguettantProduct comparison tablesZINC mg/ml zinc chloride injection, USPFDA-approved zinc injection drug productZinc injectable mg/ml, solution for infusion(translated into English)Laboratoire AguettantCompositionActive ingredientZinc Chloride, USPZinc Gluconate, USPStrength2.09 mg/mL zinc chloride equivalent to mg/mL elemental zinc 7.80 mg/mL zinc gluconate equivalent to mg/mL elemental zinc Inactive ingredientsSodium chloride mg/mLHydrochloric acid or sodium hydroxide for pH adjustmentWater for injectionsContent in aluminumNot more than 150 mcg/LNot more than 1500 mcg/L(not stated on the insert)Physiochemical parameterspH2.0 (1.5 to 2.5)5.5 to 7.0 (not stated on the insert) Osmolarity0.354 mOsmol/mL (calc.)0.30 to 0.35 mOsmol/mL(not stated on the insert)DescriptionSterile, non-pyrogenic solution intended for use as an additive to intravenous solutions for total parenteral nutrition (TPN).The solution contains no bacteriostat, antimicrobial agent or added buffer.Solution for infusion.Supplementation solution for prolonged parenteral nutrition and for prevention of severe zinc deficiency.Sterile solution(not stated on the insert)The solution contains no bacteriostat, antimicrobial agent or added buffer.(not stated on the insert)How supplied10 mL plastic vials10 mL glass vials; pack of 10 vialsStorage conditionsStore at 20 to25C(68 to77F). [See USP Controlled Room Temperature.]No special precautions for storage.Country-specific informationMarketing Authorization Number: 333 414-4Expiration date formatMM/YYYYDrug statusRx onlyNon-prescription drugAuthorization holderLaboratoire AGUETTANT1, rue Alexander Fleming69007 LYONFRANCEComparison of prescribing informationClinical pharmacology5.1 Pharmacodynamic properties5.2 Pharmacokinetic properties5.3 Preclinical safety dataZinc is an essential nutritional requirement and serves as cofactor for more than 70 different enzymes including carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase, and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration, and the senses of taste and smell.Zinc resides in muscle, bone, skin, kidney, liver, pancreas, retina, prostate and particularly in the red and white blood cells. Zinc binds to plasma albumin, a2-macroglobulin, and some plasma amino acids including histidine, cysteine, threonine, glycine, and asparagine.Ingested zinc is excreted mainly in the stool (approximately 90%), and to lesser extent in the urine and in perspiration.Providing zinc helps prevent development of deficiency symptoms such as: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly.The initial manifestations of hypozincemia in TPN are diarrhea, apathy and depression. At plasma levels below 20 mcg zinc/100 mL dermatitis followed by alopecia has been reported for TPN patients. Normal zinc plasma levels are 100 +- 12 mcg/100 mL.5.1 Pharmacodynamic propertiesINTRAVENOUS SOLUTIONS(B: BLOOD AND BLOOD FORMING ORGANS)Zinc is an essential component of at least 120 metalloenzymes including carbonic anhydrases, alkaline phosphatases, carboxypeptidases, oxidoreductases, transferases, ligases, hydrolases, isomerases and alcohol dehydrogenases.Zinc also has an important role in the synthesis of nucleic acids (DNA and RNA) and in the regulation of RNA catabolism.Zinc is involved in the transformation of T-lymphocytes and might be involved in the synthesis of insulin.Hence, zinc participates in the metabolism of carbohydrates, lipids and proteins.Zinc is indispensable for the growth of premature and full term infants and children.5.2 Pharmacokinetic propertiesNot available.5.3 Preclinical safety dataNot available.Indications and usage4.1 Therapeutic indicationsZinc mg/mL (Zinc Chloride Injection, USP) is indicated for use as supplement to intravenous solutions given for TPN.Administration helps to maintain zinc serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.Supplementation solution for prolonged parenteral nutrition and for prevention of severe zinc deficiency in conditions such as (but not limited to) severe denutrition, hypercatabolism, digestive fistula, chronic diarrhea.The supplementation scheme must cover the daily needs (3 to mg zinc per day for adults) and compensate for abnormally high losses (up to 15 mg per day).Contraindications4.3 ContraindicationsNone known.Hypersensitivity to any of the ingredients.WarningsDirect intramuscular or intravenous injection of Zinc mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.Severe kidney disease may make it necessary to reduce or omit chromium and zinc doses because these elements are primarily eliminated in the urine.WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than to mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity.Tissue loading may occur at even lower rates of administration.4.4 Special warnings and precautions for useWarningThis product must never be injected as is, but diluted in solution for infusion.4.5 Interaction with other medicinal products and other forms of interactionIn complex parenteral nutrition protocols, special precaution is required to avoid incompatibilities among the added medications.Precautions4.6 Pregnancy and lactation 4.7 Effects on ability to drive and use machines6.2 IncompatibilitiesGeneralDo not use unless the solution is clear and the seal is intact.Zinc mg/mL (Zinc Chloride Injection, USP) should only be used in conjunction with pharmacy directed admixture program using aseptic technique in laminar flow environment; it should be used promptly and in single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.Zinc should not be given undiluted by direct injection into peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of zinc from bolus injection. Administration of zinc in the absence of copper may cause decrease in serum copper levels.Laboratory TestsPeriodic determinations of serum copper as well as zinc are suggested as guideline for subsequent zinc administration.Carcinogenesis, Mutagenesis, and Impairment of FertilityLong-term animal studies to evaluate the carcinogenic potential of Zinc mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zinc mg/mL (Zinc Chloride Injection, USP) is administered to nursing woman.Pediatric UseSee DOSAGE and ADMINISTRATION section.Pregnancy Category C. Animal reproduction studies have not been conducted with zinc chloride. It is also not known whether zinc chloride can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Zinc chloride should be given to pregnant woman only if clearly needed.Geriatric UseAn evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.4.6 Pregnancy and lactation Based on available data, it is possible to use this product for pregnant or breast-feeding women. 4.7 Effects on ability to drive and use machinesNot relevant.6.2 IncompatibilitiesIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.Adverse reactions4.8 Undesirable effectsNone known.Adverse effects are observed with high dosages (see section 4.9).Drug abuse and dependence(No equivalent section)None known.Overdosage4.9 OverdoseSingle intravenous doses of to mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations.However, acute toxicity was reported in an adult when 10 mg zinc was infused over period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2 F) on the fourth day were accompanied by serum zinc concentration of 207 mcg/dl. Symptoms abated within three hours.Hyperamylasemia may be sign of impending zinc overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).Death resulted from an overdosage in which 1683 mg zinc was delivered intravenously over the course of 60 hours to 72 year old patient.Symptoms of zinc toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with serum zinc level of 4184 mcg/dl.Calcium supplements may confer protective effect against zinc toxicity.No overdose cases were reported with ZINC INJECTABLE 1mg/ml, solution for infusion.However, overdose cases by intravenous injection of zinc were reported with manifestations of acute toxicity such as profuse sweating, blurred vision, decreased level of consciousness, hypothermia, tachycardia, jaundice and pulmonary edema. Hyperamylasemia may be sign of impending zinc overdosage.Calcium supplementation may confer protective effect.Dosage and administration4.2 Posology and method of administration6.6 Special precautions for disposal and other handlingZinc mg/mL (Zinc Chloride Injection, USP) contains mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to mg zinc/day (2.5 to mL/day). An additional mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc.For full term infants and children up to years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.4.2 Posology and method of administrationEach mL contains mg of elemental zinc.The dosage must be adapted to each patient, taking into account losses and zinc status.The solution is supplementation additive for parenteral nutrition intended to be used in mixtures for parenteral nutrition or diluted in isotonic solutions.Recommended daily intakes by intravenous route are the following:- In pediatric patients:- Premature infants: 0.3 to 0.35 mg zinc/kg/day,- Full term infants: 0.1 to 0.2 mg zinc/kg/day,- Children: mg zinc/day.- In adults: to 15 mg zinc/day.6.6 Special precautions for disposal and other handlingNo special precautions. TRANSLATION OF FRENCH VIAL AND CARTON LABELSZinc injectable mg/ml, solution for infusionProduct will be distributed with the original French labelsLaboratoire AguettantZinc injectable mg/ml, solution for infusionEnglish translation for information onlyProduct will be distributed with the original French labels Laboratoire AguettantCarton Label(not stated on the label): Please refer to the package insert for the FDA-approved zinc injection drug product (zinc chloride injection, mg/mL) for full prescribing information.Vial Label(not stated on the label):Equivalent to elemental zinc mg/mL.. Zinc injectable mg/mL solution for infusion (equivalent to elemental zinc mg/mL) contains zinc gluconate trihydrate as the active substance, which is different salt than those used in other zinc drugs for injection, i.e. zinc chloride and zinc sulfate. Also, note that our manufacturer of zinc gluconate trihydrate complies with the U.S. Pharmacopoeia monograph for zinc gluconate trihydrate. We consider this formulation an appropriate alternative to the FDA-approved zinc injection drug product when used as explained below.. The composition in active substance is equivalent to one milligram of elemental zinc per milliliter of solution. The only excipient is water for injections, and the pH of the drug is comprised between 5.5 and 7.0.. No specific precautions are required for the storage of Zinc injectable mg/mL (zinc gluconate trihydrate) solution for infusion. As with your usual zinc injection drug products, you may store this at controlled room temperature 20C to 25C (68F to 77F). Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion is meant to be used by parenteral administration (infusion), only after dilution in an isotonic solution or in mixture for parenteral nutrition.. Dosing instructions for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion differ from dosing instructions for the FDA-approved zinc injection drug product. We recommend that you follow the labeling instructions for the FDA-approved zinc injection drug product.. Instructions regarding use in pregnancy for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion differ from dosing instructions for the FDA-approved zinc injection drug product. We recommend that you follow the labeling instructions for the FDA-approved zinc injection drug product.. Maximum potential aluminum content for Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion is higher than that for the FDA-approved zinc injection drug product. Consider risks of aluminum toxicity against benefit of zinc supplementation when prescribing Zinc injectable mg/mL (zinc gluconate trihydrate), solution for infusion.. Online: http://www.fda.gov/medwatch/report.htm. Regular mail: Use postage paid FDA form 3500 available at :. Fax: 1-800-FDA-0178.