NUTRINEAL™ PD4 [1.1% Amino Acid Peritoneal Dialysis
Contents
1. 674 129 677 127 1 341 135 338 131 3 181 45 a Aminobutyrate 7 5 Results from Baxter Clinical Study No DT88002 53 12 86 19 62 a Mean standard deviation units are pmol L It is also known from previous studies in the literature that amino acids absorbed from the peritoneal cavity appear rapidly in blood with a peak in concentration at one to two hours after instillation of the solution into the peritoneal cavity It may be presumed that much of the absorption is through the visceral peritoneum via the mesenteric vessels to the liver i e similar to the physiologic route of delivery of diet derived amino acids through the gut and via the portal vein After the maximum is reached the concentration declines rapidly but remains above pre exchange concentrations at four hours In Study No DT88002 which also evaluated the blood concentration of amino acids pre exchange and 4 hours post Nutrineal PD2 exchange it was determined that all amino acids originally present in the solution except glycine were greater post exchange when compared to pre exchange blood concentrations Table 4 Similarly other amino acids metabolites such as cystine and ornithine were also greater post Nutrineal PD2 exchange as compared to pre exchange concentrations These increases may also reflect the Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 19 of 31 effect of amino aci2. WARNINGS AND PRECAUTIONS Warnings Encapsulating peritoneal sclerosis EPS is considered to be a known rare complication of peritoneal dialysis therapy EPS has been reported in patients using peritoneal dialysis solutions including Nutrineal PD4 If peritonitis occurs the choice and dosage of antibiotics should be based upon the results of identification and sensitivity studies of the isolated organism s wherever possible Prior to identification of the involved organism s broad spectrum antibiotics may be indicated If any signs or symptoms of a suspected hypersensitivity reaction develop intraperitoneal administration of Nutrineal PD4 must be stopped immediately Appropriate therapeutic countermeasures must be instituted as clinically indicated Precautions General Nutrineal PD4 is intended for intraperitoneal administration only Not for intravenous administration Do not administer if the solution is discoloured cloudy contains particulate matter or shows evidence of leakage or if seals are not intact The drained fluid should be inspected for the presence of fibrin or cloudiness which may indicate the presence of peritonitis Protein amino acids water soluble vitamins and other medicines may be lost during peritoneal dialysis and may require replacement Peritoneal dialysis should be done with caution in patients with 1 abdominal conditions including disruption of the peritoneal membrane and diaphrag
3. NO gt 165 19 acid L Proline Pyrrolidine 2 carboxylic acid CsH9NO 115 13 L Serine 2 Amino 3 hydroxypropanoic C3H7NO3 105 1 acid L Threonine 2 Amino 3 hydroxybutanoic C4HoNO 119 12 acid L Tryptophan 2 Amino 3 1H indol 3 yl C1 H12N 20 204 23 propanoic acid L Tyrosine 2 Amino 3 4 hydroxyphenyl CH1 NO 181 19 propanoic acid L Valine 2 Amino 3 methylbutanoic C H NO 117 15 acid Calcium Chloride Dihydrate Calcium Chloride Dihydrate CaCle2H 0 147 01 Magnesium Chloride Hexahydrate Magnesium chloride hexahydrate MgCl e6H 0 203 30 Sodium Chloride Sodium chloride NaCl 58 44 Sodium Lactate Sodium 2 hydroxypropanoate C3H NaO3 112 07 DETAILED PHARMACOLOGY Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution contains a mixture of amino acids lactate and electrolytes sodium chloride calcium and magnesium which are currently used in approved parenteral nutrition solutions and peritoneal dialysis solutions The amino acids in Nutrineal PD4 are not new chemical entities but are naturally occurring compounds whose distribution and metabolism are well known and whose urinary excretion is negligible in patients with end stage renal disease ESRD Due to the volume of information concerning amino acid use in humans orally and parenterally and the long history of research on amino acids the nonclinical pharmacology pharmacokinetic and toxicology studies traditionally done Nutrineal PD4 1 1 Amino A
4. Do not use if pull ring is not attached to the connector 5 Inspect tubing and drainage container for presence of solution If solution is noted discard unit NOTE Small water droplets are acceptable 6 Ensure patient transfer set is closed 7 Break frangible at patient connector 8 Remove pull ring from the patient connector 9 Remove disconnect cap from patient transfer set Immediately attach patient transfer set connector to the patient connector by twisting the connector until firmly secured 10 Clamp new bag solution line 11 Break frangible at container port 12 Hang the new solution container 13 Place the drainage container below the level of the peritoneum Proceed with either Procedure A or Optional Procedure B Procedure A 14 Open transfer set clamp to drain solution from the peritoneal cavity 15 Close transfer set line clamp after drainage is complete 16 Open new solution line clamp and allow the new solution to flow into the drainage container for five seconds 17 Clamp drain line 18 Open transfer set clamp and allow the solution to flow into the peritoneal cavity 19 Close transfer set clamp when infusion is complete 20 Open a new disconnect cap following the directions accompanying the cap Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 9 of 31 21 Disconnect the patient transfer set from the TWIN BAG set and attach the new disconnect cap to the transfer set Option
5. L of 11 g of amino acids L given intraperitoneally to a 70 kg patient are absorbed in 60 min 11 g L x 2 L 70 kg 60 min 5 24 mg kg min The maximum non lethal dose in rats of 3 amino acids given a dose of 80 mL kg at a rate of 4 mL min and average body weight of 200 g is equivalent to a dose of 600 mg kg min Thus the margin of safety is 600 mg kg min 5 24 mg kg min 114 This margin of safety is an underestimate because the acute mechanism of toxicity vascular hypervolemia is not achievable by the intraperitoneal route of administration Table 7 Intravenous Acute Toxicity of 3 Essential Amino Acids Solution Species and Strain Number of Animals amp Dosage mL kg Number of Deaths Sex Group Rat Sprague Dawley 10M 10F 40 none Rat Sprague Dawley 6M 10F 80 none Rat Sprague Dawley 10M 10F 120 4M Reference Final Report R D 01 101 CC1101B Oct 31 1973 3 essential amino acid solution was injected intravenously at a rate of 4 ml min The acute toxicity of amino acids administered individually or in mixtures was studied in order to develop an amino acid solution suitable for parenteral injection in humans Male rats were given intraperitoneal injections of aqueous solutions or suspensions of crystalline amino acids The dosages required for 50 lethality in rats range from 3 7g per kg body weight except for L tryptophan which has a LDso of 1 6 g per kg body weight see Table 8 Large d
6. Studies Acute Toxicity Acute toxicity studies of highly purified amino acids were conducted as part of a 5 day subacute toxicity study in Sprague Dawley rats The data are summarized in Table 7 see below The Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 21 of 31 results showed that four of ten male rats injected intravenously at a dose of 120 mL kg body weight and a rate of 4 mL min of a 3 amino acid solution died immediately following the injection There were no deaths in the female rats Deaths were attributed to pulmonary hemorrhage resulting from the large injection volume There was no local damage at the site of injection The mechanism of toxicity was judged to be attributable to volume overload of the vascular system Since the total blood volume of a rat is approximately 7 of body weight infusion of 120 mL kg at a rapid rate is equivalent to increasing the blood volume to 190 mL kg from 70 mL kg or 2 7 fold The outcome of pulmonary hemorrhage and death is expected because of the limited capacity of the vascular system and rupture at the weakest vascular walls the capillaries of the lung This study shows the maximum non lethal dose is greater than 80 mL kg and the minimum lethal dose is less than 120 mL kg The margin of safety is determined by comparing the no observed effect dose in the animal toxicity study with the clinical dose The usual clinical dose of 1 1 amino acids is 5 24 mg kg min assuming 2
7. bacterial IMMUNE SYSTEM DISORDERS Hypersensitivity METABOLISM AND NUTRITION DISORDERS Anorexia GASTROINTESTINAL DISORDERS Abdominal pain Peritonitis Peritoneal cloudy effluent Abdominal discomfort SKIN AND SUBCUTANEOUS DISORDERS Angioedema Pruritus GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Catheter related complication Pyrexia Malaise INVESTIGATIONS Peritoneal fluid analysis abnormal DRUG INTERACTIONS No interaction studies have been conducted with NUTRINEAL Blood concentration of other dialyzable medicinal products may be reduced during dialysis There is no incompatibility between heparin or insulin and Nutrineal PD4 in the VIAFLEX container In case of medicinal product admixture compatibilities must be checked before use and admixed solution must be used immediately Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 7 of 31 DOSAGE AND ADMINISTRATION Recommended Dose and Dosage Adjustment Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution is intended for intraperitoneal administration only substituting for one or two of the dextrose containing exchanges per day as part of the daily dialysis regimen for patients with protein malnutrition Adequate dialysis should be established prior to initiation of treatment with Nutrineal PD4 Adults and Elderly e One peritoneal dialysis Nutrineal PD4 exchange per day of one 2 0 liter or one 2 5 liter bag is
8. in this leaflet please tell your doctor SERIOUS SIDE EFFECTS HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Talk with your Stop taking doctor or drug and Symptom effect pharmacist seek emergency E In all medical cases severe Very e Nausea Common vomiting anorexia nausea abdominal pain symptoms for gastrointestinal disorders e Body swelling symptoms for increase in body fluid volume Common po AA e Shortness of breath e Dizziness drop in blood pressure symptoms for decrease in body fluid volume e Anemia symptoms like weakness or fatigue general malaise and sometimes poor concentration e Depression vf Y swelling soreness around catheter site symptoms for catheter site infection Unknown e Allergic reactions 4 symptoms like lumpy skin rash or hives anywhere angioedema pruritus on the body i e Abdominal discomfort peritoneal cloudy effluent fever symptoms for inflammation of the peritoneum Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 30 of 31 HOW TO STORE IT Protect from light until ready to use Store at 15 25 C Protect Nutrineal PDA from freezing Do not remove from the carton until ready for use Any unused portion of the solution should be discarded Keep out of sight and reach of children REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associa
9. must be used immediately Peritoneal dialysis solutions may be warmed in the overpouch to 37 C 98 6 F to enhance patient comfort However only dry heat for example heating pad warming plate should be used Solutions should not be heated in water or in a microwave oven due to the potential for patient injury or discomfort Do not administer unless the solution is clear and free of particulate matter Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 8 of 31 The drained fluid should be inspected for the presence of fibrin or cloudiness which may indicate the presence of peritonitis Discard any unused remaining solution For single use only Directions for Use Aseptic technique should be employed throughout the peritoneal dialysis procedure For complete system preparation see directions accompanying ancillary equipment Preparation and Administration for the Single Bag Container Follow the instructions in user manual or directions accompanying tubing sets and devices for automated peritoneal dialysis Preparation and Administration for the TWIN BAG Container 1 Do not remove from the carton until ready for use 2 Remove container from overpouch 3 Inspect solution container and frangible to ensure that there are no leaks and the solution has not expired If leaks are detected or the expiration date has lapsed discard container 4 Inspect the patient connector to ensure the pull ring is attached
10. no data L Valine 46 7 5389 Gullino et al 19560 Milne 1968 Lewis RJ Tatken RL 19822 Repeat Dose Toxicity The repeat dose toxicity of Nutrineal PD2 and similar peritoneal dialysis and intravenous solutions was assessed in a series of studies including intraperitoneal administration and intravenous administration In a 28 day intraperitoneal study in rats Baxter Study No R062830524 groups of 10 animals received doses of a 1 or 2 purified amino acid solution nearly twice that in the proposed drug product with electrolytes in a Dianeal PD 2 formulation at a dose of 30 mL kg The solution was administered intraperitoneally four times per day for a total daily dose of up to 120 mL kg A control group received a solution without amino acids or dextrose e g sterile water plus electrolytes in a Dianeal PD 2 formulation and a reference group included a solution consisting of Dianeal PD 2 with 4 25 dextrose A fifth group received the 2 purified amino acid solution with electrolytes in a Dianeal PD 2 formulation twice a day The infused solutions were not drained as is the procedure in the clinical setting No adverse toxicological findings were observed A slightly higher spleen weight was seen in the animals treated with the solution with dextrose reference group Abdominal adhesions noted to some extent in all groups were attributed to the use of indwelling peritoneal catheters used to deliver the solu
11. the recommended dose for a 70 kg body weight patient In smaller patients the fill volume may need to be reduced depending on body size In exceptional cases a different regimen may be indicated but the dose should not exceed two exchanges per day e Note that the recommended daily total intake of proteins is greater than or equal to 1 2 g kg body weight for adult dialysis patients A 2 0 liter bag of Nutrineal PD4 contains 22 g of amino acids which corresponds to 0 30 g kg body weight 24 h approximately 25 of the daily protein requirements for an adult dialysis patient of 70 kg body weight Children and Adolescents e Safety and effectiveness in pediatric patients has not been established If Nutrineal PD4 is used the recommended dose is one peritoneal dialysis exchange per day The risk benefit ratio should be assessed and the dialysis prescription and appropriate adaptation of fill volume must be individualized Administration Nutrineal PD4 is intended for intraperitoneal administration only Not for intravenous administration The mode of therapy frequency of treatment exchange volume duration of dwell and length of dialysis should be initiated and supervised by the prescribing physician Treatment should be re evaluated after 3 months if there is no clinical or biochemical improvement in the status of the patient In case of medicinal product admixture compatibilities must be checked before use and the admixed solution
12. treatment started For example if you have an infection your doctor may perform some tests to find out which antibiotic will be best for you Until your doctor knows which infection you have he may give you an antibiotic that is effective against a wide number of different bacteria This is called a broadspectrum antibiotic If any signs or symptoms of an allergic reaction develop Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 28 of 31 intraperitoneal administration of Nutrineal PD4 must be stopped immediately Your doctor might need to treat your allergy immediately Other Warnings During peritoneal dialysis your body may lose protein amino acids and vitamins Your doctor will know if these need to be replaced A rare complication of peritoneal dialysis called encapsulating peritoneal sclerosis EPS may occur after being treated with perioneal dialysis for an extended period of time Symptoms and signs are usually nonspecific but may include severe abdominal pain inability to remove fluid persistent nausea and vomiting and intestinal blockage Diagnosis is confirmed by your doctor Your doctor should check your potassium levels regularly If they fall too low your doctor may give you some potassiumto compensate Your doctor should advise you about particular precautions as they apply to you Your doctor should monitor your blood parameters at regular intervals and ensure that they are a
13. 17 Clamp drain line 18 Open new solution line and allow solution to flow into the peritoneal cavity 19 Close transfer set clamp when infusion is complete 20 Open a new disconnect cap following the directions accompanying the cap 21 Disconnect the patient transfer set from the TWIN BAG set and attach the new disconnect cap to the transfer set Nutrineal PD4 should be infused based on your need for adequate dialysis as determined by your doctor When draining the fluid after the dwell always check your drained fluid for cloudiness or fibrin Fibrin looks like clumps or stringy material in the drained solution Cloudy drained fluid or fibrin may mean you have an infection Call your doctor if your drained fluid is cloudy or contains fibrin Ifyou infuse too much NUTRINEAL you may get abdominal distension a feeling of fullness Contact your doctor immediately He will advise what to do Overdose Overdose may result in fluid overload and or electrolyte imbalances In case of drug overdose contact a health care practitioner hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms SIDE EFFECTS AND WHAT TO DO ABOUT THEM Like all medications Nutrineal PD4 may cause side effects Side effects may inlcude feeling of weakness headache fever malaise and asthenia If any of the side effects become serious or if you notice any side effects not listed
14. 3 13 16 13 7 5 TEF NA Results from Baxter Clinical Study No DT88002 Mean standard deviation units are in pmol L ab Differs from Day 16 P lt 0 01 and P lt 0 05 respectively Differs from Day 26 P lt 0 05 NA Not Available AF Data from 12 normal subjects with normal renal function obtained from Central Amino Acid Laboratory University of Iowa Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 20 of 31 In Study No RD 92 CA 042 the chronic effects of Nutrineal PD2 on the plasma amino acid profile were compared to those with dextrose Dianeal Over a three month treatment period patients in the Nutrineal PD2 treated group showed significant increases in pre exchange plasma concentrations of histidine threonine valine ornithine and serine compared to patients in the Control Group who received only dextrose dialysis solution Table 6 There was also a marginal increase in lysine concentration p 0 069 As in the previous study Study No DT88002 all but ornithine had been abnormally low before treatment and these increases brought them closer to the normal range Ornithine increased because it is a normal metabolite of arginine which was present in Nutrineal PD2 Also as was observed in the nitrogen balance study Study No DT88002 plasma taurine decreased during treatment with Nutrineal PD2 Table 6 Changes in Pre exchange Plasma Amino Acid Concentrations in Controls and in Patients Treat
15. P Sodium Chloride USP Sodium Lactate Excipients Water for Injection USP Hydrochloric acid for pH adjustment Concentration of ions Amino Acids Sodium Calcium Magnesium Chloride Lactate 50 9 mg 30 mg 18 3 mg 5 08 mg 538 mg 448 mg qs qs 87 mmol L 132 mmol L 1 25 mmol L 0 25 mmol L 105 mmol L 40 mmol L Includes additional contributions from lysine hydrochloride and hydrochloric acid used for pH adjustment pH adjusted with hydrochloric acid 6 6 5 7 to 6 8 Calculated osmolarity approx 365 mOsm L Nutrineal PD4 is available in TWIN BAG containers holding 2000 mL or 2500 mL and Single Bag containers holding 2500 mL Nutrineal PDA 1 1 Amino Acid Peritoneal Dialysis Solution Page 13 of 31 PART II SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper Name Chemical Name Molecular Formula Molecular Mass L Alanine 2 Aminopropanoic acid C3H7NO gt 89 09 L Arginine 2 Amino 5 guanidinopentanoic C H14N405 174 2 acid Glycine Aminoethanoic acid C H NO 75 07 L Histidine 2 Amino 3 1H imidazol 4 yl C H N30 155 16 propanoic acid L Isoleucine 2 Amino 3 methylpentanoic C H NO 131 17 acid L Leucine 2 Amino 4 methylpentanoic CH 3NO 131 18 acid L Lysine HCl 2 6 Diaminohexanoic acid C H14N 20 182 65 L Methionine 2 Amino 4 methylthio butanoic C H NO S 149 21 acid L Phenylalanine 2 Amino 3 phenylpropanoic CoH
16. PRODUCT MONOGRAPH NUTRINEAL PD4 1 1 Amino Acid Peritoneal Dialysis Solution Peritoneal Dialysis Solution Baxter Corporation Date of Revision 7125 Mississauga Road Mississauga ON July 30 2012 L5N 0C2 www baxter ca Submission Control No 155366 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page l of 31 Table of Contents PART I HEALTH PROFESSIONAL INFORMATION cccsssssssssssssssssssssssssessessessesseees 3 SUMMARY PRODUCT INFORMA TION soda di 3 INDICATIONS AND CUINIG AL US Brissia tds 3 CONTRAINDICATIONS 000 A ea 3 WARNINGS AND PRECAUTION Sada 4 ADVERSE REACTIONS stand A aaa 6 DRUG INTERACTIONS a A A A 7 DOSAGE AND ADMINISTRATION cnini neit adi ai iiaia 8 OVERDOS AGE 00000 RA Sees 10 ACTION AND CLINICAL PHARMACOLOGY csi 10 STORAGE AND SAB LGU mcer eane A a E 12 SPECIAL HANDLING INSTRUCTIONS sesessseeessesesersrrerssrsresreseeresresrestssesresesresreseerese 12 DOSAGE FORMS COMPOSITION AND PACKAGING ccococinccncnconcconicnonnninnanininnncnnos 12 PART II SCIENTIFIC INFORMATION scsssccsesssacsssscsscesecceosstestuecestcsousscuecsscsscectesenecdsvevsbescuee 14 PHARMACEUTICAL INFORMA TION scsi ac 14 DETAILED PHARMACOLOGY isto cases aotearoa iia ad adi Cag aii 14 TOXICOLOGY 000 A AAA A A 21 REFERENC Pita ai AA AS 26 PART III CONSUMER INFORMATION occcccoocononnoononnoonoonconconconconnoncoonoonconconccnconconccnncnaconoss 28 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solu
17. Solution is 346 mOsmol L Nutrineal PD4 is therefore an effective alternate osmotic agent The amino acid mixture is composed of 64 essential and 36 nonessential amino acids by weight Some of the nonessential amino acids i e tyrosine serine arginine are included in the solution specifically because their biosynthesis from other substrates may be impaired in dialysis patients The amino acids in Nutrineal PD4 are absorbed into the blood and are substrates for synthesis of proteins both constituent and functional Many patients with chronic renal failure display evidence of protein or protein calorie malnutrition related to reduced protein and energy intake and increased protein and energy requirements During conventional peritoneal dialysis with dextrose based solutions there is an expected loss of amino acids and proteins into the spent dialysate Nutrineal PD4 provides amino acids in the dialysis solution to compensate for unavoidable losses of protein and amino acids into the dialysate This improves abnormal plasma amino acid profiles frequently observed in patients in chronic renal failure The maintenance of adequate nutrition in peritoneal dialysis patients has been found to reduce the incidence of peritonitis and to minimize the length of hospitalization Since one of the complications of renal failure is decreased ability to eliminate phosphate Nutrineal PD4 provides a biologically utilizable phosphate free source mat
18. al Procedure B 14 Open new solution line clamp and allow the new solution to flow into the drainage container for five seconds 15 Clamp new solution line 16 Open transfer set clamp to drain solution from the peritoneal cavity 17 Clamp drain line 18 Open new solution line and allow solution to flow into the peritoneal cavity 19 Close transfer set clamp when infusion is complete 20 Open a new disconnect cap following the directions accompanying the cap 21 Disconnect the patient transfer set from the TWIN BAG set and attach the new disconnect cap to the transfer set In the Event That Supplemental Medication is Prescribed 1 Inspect container to ensure resealable rubber medication port is in place Discard if rubber medication port is not attached to container port 2 Prepare medication port according to aseptic technique 3 Using a syringe with a one inch long 19 to 25 gauge needle puncture resealable medication port and inject medication 4 Position container with medication port facing upward Squeeze and tap medication port to empty solution Mix solution by vigorously agitating container OVERDOSAGE For the management of suspected overdose contact your regional poison control centre There is potential for overdose resulting in hypervolemia and electrolyte disturbances Management of Overdose e Hypervolemia may be managed by using hypertonic peritoneal dialysis solutions and fluid restriction e Electr
19. ble to the amino acid content gt Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 25 of 31 REFERENCES l 10 11 Slatopolsky E Weerts C Norwood K Giles K Fryer P Finch J Windus D Delmez J Long term effects of calcium carbonate and 2 5 mEq liter calcium dialysate on mineral metabolism Kidney Int 1989 Nov 36 5 897 903 Shaw SN Elwyn DH Askanazi J Iles M Schwarz Y Kinney JM Effects of increasing nitrogen intake on nitrogen balance and energy expediture in nutritionally depleted adult patients receiving parenteral nutrition Am J Clin Nutr 1983 Jun 37 6 930 40 Oreopoulos DG Marliss E Anderson GH Oren A Dombros N Williams P Khanna R Rodella H Brandes L Nutritional aspects of CAPD and the potential use of amino acid containing dialysis solutions Perit Dial Bull 1983 3 S10 2 Twardowski Z Khanna R Nolph K Osmotic agents and ultrafiltration in peritoneal dialysis Nephron 1986 42 2 93 101 Goodship TJ Lloyd S McKenzie PW Earnshaw M Smeaton I Bartlett K Ward MK Wilkinson R Short term studies on the use of amino acids as an osmotic agent in continuous ambulatory peritoneal dialysis Clin Sci 1987 Nov 73 5 471 8 Anderson GH Patel DG Jeejeebhoy KN Design and evaluation by nitrogen balance and blood aminograms of an amino acid mixture for total parenteral nutrition of adults with gastrointestinal disease J Clin Invest 1974 Mar 53 3 904 12 Fenton SS Johnst
20. ce of the adverse event was gt 2 higher compared to the control group Clinical Trial Adverse Events System Organ Class SOC Preferred MedDRA Frequency Percentage Term of Patients INFECTIONS AND INFESTATIONS Catheter site infection Common 8 9 Infection Common 5 1 BLOOD AND LYMPHATIC SYSTEM Anemia Common 6 3 DISORDERS METABOLISM AND NUTRITION Acidosis Very Common 35 4 DISORDERS Hypervolemia Very Common 13 9 Hypokalemia Common 8 9 Hypovolemia Common 6 3 PSYCHIATRIC DISORDERS Depression Common 5 1 RESPIRATORY THORACIC AND Dyspnea Common 6 3 MEDIASTINAL DISORDERS GASTROINTESTINAL DISORDERS Nausea Vomiting Very Common 19 0 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 6 of 31 Anorexia Very Common 15 2 Nausea Very Common 15 2 Gastritis Common 5 1 GENERAL DISORDERS AND Asthenia Very Common 10 1 ADMINISTRATION SITE CONDITIONS INVESTIGATIONS Blood urea increased Very Common 15 2 Frequency is based upon the following scale Very Common gt 1 10 Common 21 100 lt 1 10 Uncommon 21 1 000 lt 1 100 Rare 21 10 000 lt 1 1 000 Very Rare lt 1 10 000 The term nausea and vomiting is not available in MedDRA 11 0 The term has been retained to reflect the available source data Post Market Adverse Drug Reactions The following adverse reactions have been reported in the post marketing experience INFECTIONS AND INFESTATIONS Peritonitis
21. centrations and dialysate effluent volumes were measured at the end of a 4 hour exchange with Nutrineal PD2 on the Ist 9th and 19th days of treatment Net absorption was obtained by subtracting the mass remaining at four hours volume multiplied by concentration from the mass infused volume infused multiplied by concentration in Nutrineal PD2 Percent net absorption percent uptake was calculated as the mass absorbed divided by the mass infused multiplied by 100 The results are shown in Table 2 The mean percent net absorption or percent uptake at four hours ranged from 77 for lysine and histidine to 85 for methionine This value for any amino acid was essentially the same on all three days in which it was assessed The reproducibility of these numbers attests to the lack of any effect of the solution upon the transport characteristics of the peritoneal membrane The total grams of amino acids absorbed can be calculated from the data in Table 2 and the amino acid content of Nutrineal PD2 as shown in Table 3 The percent net absorption of amino acids over a four hour exchange was 17 53 22 00 x100 equals 79 7 or approximately 80 Table 2 Mean Percent Net Absorption of Amino Acids Amino Acid Day of Treatment with Nutrineal PD2 Day of Study 1 16 9 26 19 35 Histidine 77 76 77 Isoleucine 83 81 83 Leucine 84 82 84 Lysine 77 74 76 Methionine 85 84 85 Phenylala
22. cid Peritoneal Dialysis Solution Page 14 of 31 as part of new drug development have not been conducted as part of the development program for Nutrineal PD4 Several pharmacology and nonclinical toxicology studies have been conducted with Nutrineal PD2 In addition several nonclinical studies have been conducted with other peritoneal dialysis solutions or intravenous solutions that are similar in composition to Nutrineal PD4 and provide valuable supporting data on the safety of amino acid based peritoneal dialysis solutions All solution formulations are presented in Table 1 Table 1 Quantitative Composition of Nutrineal PD4 Compared to Other Peritoneal Dialysis Solutions and Intravenous Solutions g litre Ingredient Formulation Method of Administration 3 EAA 5 SAAS 1 AA 2 AA Nutrineal Dianeal PD2 G L PDZ ip PD2 ip PD2 ip w dextrose ip 11 otal amino acids tyrosine valine cystine glutamic acid L aspartic acid hexahydrate Sodium acetate Sodium lactate Sodium chloride EAA essential amino acids SAAS synthetic amino acid solution AA amino acids iv intravenous ip intraperitoneal Solution used in Study No R D 01 101 CC1101B Solution used in Study No R D 1 101A CC1101A Solution used in Study No RO62830524 Solution used in Study No RO62830524 contained 42 5 g L dextrose Lysine added to th
23. consistent with an increase in plasma glucose Lactic acid and urine nitrogen were also increased as was urinary glucose There were no effects discernible that would have been associated with the amino acids although they could have contributed to the increased urea nitrogen levels due to the nitrogen content of amino acids In the 30 day study with dogs a 5 synthetic amino acid solution SAAS was administered intravenously at 40 and 100 mL kg five days per week In this study both of these doses were well tolerated the only indication of a treatment related effect was an increase in serum urea nitrogen that was likely related to the administered nitrogen content associated with amino acid administration There were no clinical hematological organ weight body weight or histopathological changes attributable to the administered amino acid solution Reproductive Toxicology Reproduction and teratology studies have not been conducted with Nutrineal PD4 This is because the stress associated with an intraperitoneal route of administration would obscure appropriate scientific evaluation of these studies Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 24 of 31 The effect of an oral diet of highly purified amino acids on growth reproduction embryotoxicity and lactation was studied in rats The purified amino acids were mixed with salts minerals and electrolytes vitamins B and C and glucose prepared in 50 aq
24. dequate during your treatment Together with your doctor keep a record of your dietary protein intake your fluid balance and your body weight INTERACTIONS WITH THIS MEDICATION Tell your doctor if you are taking or have recently taken any other medications including medications obtained without a prescription If you use other medications your doctor may need to increase their dose This is because peritoneal dialysis treatment increases the elimination of certain medications Be cautious if you use heart medications known as cardiac glycosides e g digoxin Your heart medications may not be as effective or its toxicity may be increased You may need potassium and calcium supplements develop an irregular heartbeat an arrhythmia Your doctor should monitor you closely during treatment especially your potassium levels PROPER USE OF THIS MEDICATION Usual Adult dose Your doctor should prescribe you the appropriate number of bags you must use Usually it varies from one bag of 2 0 litres to one bag of 2 5 litres every day If you are below 18 years of age your doctor should assess carefully the prescription of Nutrineal PD4 Your doctor should re evaluate your treatment after 3 months if there is no improvement in your nutritional status Aministration Instructions To do your Nutrineal PD4 exchange it is very important that you follow the steps shown to you in your training All surfaces and connecti
25. ds absorbed from food proteins as patients ate during the early portion of the exchange The effects of treatment with Nutrineal PD2 on the amino acid profile during the 20 days of treatment were also investigated Plasma samples were obtained on Day 16 prior to the first instillation of Nutrineal PD2 on the first day of treatment Day 26 after ten days of treatment and Day 35 on the 20th day of treatment The results are shown in Table 5 Between Days 16 and 26 there were significant increases in histidine lysine threonine valine cystine arginine citrulline ornithine and proline and a decrease in taurine Between Days 26 and 35 there was a further increase in cystine and a further decrease in taurine Table 5 Pre exchange Plasma Amino Acid Concentrations during Treatment with Nutrineal PD2 N 21 N 19 N 18 Essential Amino Acids 66 125 76 14 88 10 59 14 60 10 86 20 89 18 160 32 137 24 10 2244 56 17 53 19 117 34 132 36 20 11 21711 141 30 187 30 Semi Essential Amino Acids 59 24 63 20 34 10 35 12 Nonessential Amino Acids 394 130 402 128 433 166 79 20 95 23 99 22 45 11 44 11 48 13 14 6 1647 88 25 98 26 46 22 53 22 40 19 39 2 674 129 689 123 480 133 341 135 288 102 265 118 53 12 62 18 66 28 181 45 203 47 210 65 69 18 71414 108 24 69 30 55 23 48 18 37 12 3
26. e formulation as lysine HCl but analytically measured and reported as lysine Nutrineal PD4 with 1 1 amino acids has 0 183 g L calcium chloride dihydrate Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 15 of 31 The amino acids and electrolytes contained in Nutrineal PD4 are present naturally in the foods consumed by humans These ingredients have been tested in numerous biological systems and been the focus of biological research for several centuries In foods amino acids are chemically bonded together to form proteins After oral ingestion the proteins are hydrolyzed to amino acids in the digestive tract and these are then absorbed into the portal blood stream During intraperitoneal administration the amino acids from Nutrineal PD4 are absorbed across the peritoneal membrane and are transported via the portal circulation first through the liver and then out into the peripheral tissues Nutritional studies conducted during the period of approximately 1900 1960 defined the amino acid requirements for various species the metabolic processes by which the body handles them and their acceptable levels of intake The composition of Nutrineal PD4 is based on this well established data In a controlled clinical study in an outpatient setting Baxter Clinical Study No RD 92 CA 042 there was a statistically significant p lt 0 05 overall improvement in nutritional status over a three month study period a
27. ed with Nutrineal PD2 Study No RD 92 CA 042 Change at Three Months from Baseline Controls N 55 Nutrineal PD2 N 57 0 006 0 004 0 000 Omithine PB 0 006 0 003 0 018 Since the peritoneal membrane is more permeable to large molecules than the synthetic or semi synthetic membranes used in hemodialysis losses of proteins and amino acids into peritoneal dialysate are significant Various studies with amino acid dialysis solutions have shown conclusively that amino acids are efficiently absorbed from the peritoneal cavity Since the fractional absorption is approximately 80 over 4 5 hours one exchange with 2 L of a solution 1 0 or greater in amino acid content can easily replace the 3 4 g of amino acids and 8 10 g of proteins normally lost during peritoneal dialysis Due to the loss of proteins during peritoneal dialysis the protein requirement of an average sized Continuous Ambulatory Peritoneal Dialysis CAPD patient is increased by about 0 2 g protein per kg body weight per day Peritonitis can transiently increase these peritoneal protein losses by 2 fold or more TOXICOLOGY Human Studies High dose intravenous amino acid infusions were studied in humans and found to have no adverse reactions or gross abnormalities with respect to amino acid metabolism when single essential amino acids tryptophan leucine and methionine were administered at up to 2 5 g kg body weight in a 6 10 hour period Animal
28. ely that these minor losses will lead to clinically significant changes within the expiration period The amount of water that can permeate from inside the solution container into the overpouch is insufficient to affect the solution significantly Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts however biological testing was supportive of the safety of the plastic container materials SPECIAL HANDLING INSTRUCTIONS See STORAGE AND STABILITY DOSAGE FORMS COMPOSITION AND PACKAGING Nutrineal PD4 is a sterile nonpyrogenic solution of essential and nonessential amino acids and electrolytes supplied in Baxter Corporation s PL 146 container system Nutrineal PD4 is for intraperitoneal administration only and contains no bacteriostatic or antimicrobial agents Each 100 mL of Nutrineal PD4 contains Essential Amino Acids Histidine USP 71 4 mg Isoleucine USP 84 9 mg Leucine USP 101 9 mg Lysine added as Lysine HCl USP 95 5 mg Methionine USP 84 9 mg Phenylalanine USP 57 mg Threonine USP 64 5 mg Tryptophan USP 27 mg Valine USP 139 3 mg Nonessential Amino Acids Alanine USP 95 1 mg Arginine USP 107 1 mg Glycine USP 50 9 mg Proline USP 59 5 mg Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 12 of 31 Serine USP Tyrosine USP Electrolytes Calcium Chloride Dihydrate USP Magnesium Chloride Hexahydrate US
29. erial for protein synthesis Pharmacodynamics Nutrineal PD4 is a sterile and non pyrogenic solution which when used in peritoneal dialysis enables the removal of toxic substances produced by nitrogen metabolism and normally excreted by the kidneys and facilitates the regulation of fluid and electrolytes as well as acid base balance The concentration of electrolytes in the fluid is similar except for lactate to the electrolyte composition of normal extra cellular fluid Pharmacokinetics The solution is instilled in the peritoneal cavity and then drained after a dwell time as prescribed by the physician The solution takes effect across the peritoneal membrane according to the principles of osmotic diffusion Seventy to eighty percent 70 80 of the amino acids infused are absorbed after 4 6 hours of dwell in the peritoneal cavity Electrolytes follow the standard metabolism of each ion Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 11 of 31 STORAGE AND STABILITY Protect from light until ready to use Exposure of pharmaceutical products to heat should be minimized Store at 15 25 C Do not remove from carton until ready to use The plastic TWIN BAG solution container system is fabricated from polyvinyl chloride PL 146 Plastic Exposure to temperatures above 30 C during transport and storage will lead to minor losses in moisture content Higher temperatures lead to greater losses It is unlik
30. ificance of the Amino Acids Physiol Rev 1938 18 109 36 15 Conner MW Newberne PM Drug Nutrient Interactions and their Implications for Safety Evaluation Fundam Appl Toxicol 1984 Jun 4 3 Pt 2 S341 56 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 27 of 31 PART Ill CONSUMER INFORMATION Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution This leaflet is Part III of a three part Product Monograph published when Nutrineal PD4 was approved for sale in Canada and is designed specifically for consumers This leaflet is a summary and will not tell you everything about Nutrineal PD4 Contact your doctor or pharmacist if you have any questions about the drug ABOUT THIS MEDICATION What the medication is used for Nutrineal PD4 is a sterile peritoneal dialysis solution for the treatment of protein malnutrition It does not contain glucose It is prescribed for you for your protein malnutrition and also have kidney failure which requires peritoneal dialysis It may replace one or two of the dextrose containing dialysis solutions during a one day period What it does Nutrineal PD4 contains amino acids that are absorbed into the blood during peritoneal dialysis and serve as building blocks from which the body can make protein Nutrineal PD4 draws fluid and wastes from your blood stream into your peritoneal cavity This is the cavity in your abdomen belly between your skin and
31. ize WARNINGS AND PRECAUTIONS What you should tell your doctor before using Nutrineal PD4 If you have severe disorders affecting fat digestion If you have problems affecting your abdominal wall or cavity For example if you have a hernia or an infection Ifyou had aortic graft placement If you have severe lung disease e g emphysema If you have severe breathing difficulties If you use insulin or any other treatments for correcting hyperglycemia Your doctor may need to adjust their dose Ifyou are undergoing treatment for secondary hyperparathyroidism your doctor will decide if you can use a dialysis solution with a low calcium content If you are pregnant or breastfeeding Nutrineal PDA is not recommended during pregnancy or while breast feeding unless your doctor advises differently Tell your doctor immediately if the following occurs while taking Nutrineal PD4 If you experience loss of appetite nausea or vomiting Your doctor may need to reduce the number of Nutrineal PD4 exchanges or stop Nutrineal PD4 treatment Ifyou experience abdominal pain or notice cloudiness haziness or particles in the drained fluid This may be a sign of peritonitis inflamed peritoneum or infection You should contact your medical team urgently Note the batch number and bring it along with the drained fluid bag to your medical team They will decide if the treatment should be stopped or any corrective
32. m by surgery from congenital anomalies or trauma until healing is complete abdominal tumors abdominal wall infection hernias fecal fistula or colostomy large polycystic kidneys or other conditions that compromise the integrity of the abdominal wall abdominal surface or intra abdominal cavity and 2 other conditions including aortic graft placement and severe pulmonary disease Overinfusion of a peritoneal dialysis solution into the peritoneal cavity may be characterized by abdominal distension abdominal pain and or shortness of breath Treatment of peritoneal dialysis solution overinfusion is to drain the solution from the peritoneal cavity Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 4 of 31 Potassium is omitted from Nutrineal PD4 solutions due to the risk of hyperkalemia In situations in which there is a normal serum potassium level or hypokalemia the addition of potassium chloride up to a concentration of 4 mEq L may be indicated to prevent severe hypokalemia and should be made after careful evaluation of serum and total body potassium only under the direction of a physician Additives may be incompatible See DOSAGE amp ADMINISTRATION Carcinogenesis and Mutagenesis Long term animal studies with Nutrineal PD4 have not been performed to evaluate the carcinogenic or mutagenic potential Renal Use of Nutrineal PD4 can result in elevation of blood urea nitrogen BUN uremic signs and
33. mong the Nutrineal PD2 treated patients compared to the control patients based on the proportion of patients showing improvement from baseline in two or more of the five efficacy parameters e g albumin prealbumin total protein transferrin and mid arm muscle circumference The proportion of patients showing overall improvement was 70 for the Nutrineal PD2 group and 45 for the control group The difference in nutritional status between the Nutrineal PD2 patients and the control patients was most pronounced at month 1 differences between the two groups were significant p lt 0 056 or well below for all four parameters albumin prealbumin total protein and transferrin measured Additionally analysis of insulin like growth factor 1 IGF 1 another indicator of nutritional status showed a statistically significant p lt 0 003 difference between the Nutrineal PD2 and control patients at month 3 The peritoneal equilibration test PET which measures the transport characteristics of the peritoneal membrane showed no statistical or clinically significant differences between the Nutrineal PD2 and control groups in ultrafiltration volume or peritoneal membrane mass transfer area coefficients for glucose urea creatinine and total protein after three months as well as at six months in eight patients who received Nutrineal PD2 for that long Therefore the use of Nutrineal PD2 for up to six months had no deleterious effec
34. ng parts must be clean to avoid serious infection If you need more help or have any questions you should contact your doctor Before use warm the bag to 37 C Use only dry heat for example a heating pad or warming plate Never immerse in water to warm the bag Never use a microwave oven to warm the bag Use only if the solution is clear and the container undamaged Use aseptic technique throughout the administration of the solution Aseptic technique is the effort taken to keep yourself from micro organisms infection Use each bag only once Discard any unused remaining solution Preparation and Administration for the Single Bag Container Follow the instructions in user manual or directions accompanying tubing sets and devices for automated peritoneal dialysis Preparation and Administration for the TWIN BAG Container 1 Do not remove from the carton until ready for use 2 Remove container from overpouch 3 Inspect solution container and frangible to ensure that there are no leaks and the solution has not expired If leaks are detected or the expiration date has lapsed discard container 4 Inspect the patient connector to ensure the pull ring is attached Do not use if pull ring is not attached to the connector 5 Inspect tubing and drainage container for presence of solution If solution is noted discard unit NOTE Small water droplets are acceptable Ensure patient transfer set is closed Break f
35. nine 79 77 78 Threonine 80 78 80 Tryptophan 80 78 79 Valine 80 78 79 Tyrosine 78 76 78 Alanine 81 79 81 Arginine 78 76 77 Glycine 81 79 81 Proline 79 76 79 Serine 82 80 82 Results from Baxter Clinical Study No DT88002 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 17 of 31 Table 3 Net Amino Acid Absorption during a 4 hr Exchange with Nutrineal PD2 Tyrosine OP Alanine SB Glycine 8 gt Total 00S Mean of Days 16 26 and 35 The percent absorption was directly correlated with the dialysate plasma D P creatinine ratio a measure of membrane transport characteristics for small molecules measured by a specific protocol in a four hour peritoneal solute equilibration test The D P ratio is a measure of the extent to which equilibration between blood and dialysate is achieved over four hours and this quantity varies from patient to patient The data indicate that in general absorption of amino acids from the peritoneal cavity in an individual patient was governed by the transport properties of that patient s peritoneal membrane Generally the higher the D P ratio the higher the percent amino acid uptake A similar relationship exists between D P creatinine and the dextrose absorption from the dextrose based dialysis solutions The percent net absorption of amino acids from Nutrineal PD2 is essentially the same as that found in studies with other similar amino acid peri
36. ns were limited to transient hyperkinesia and hyperpnea with no significant signs of toxicity This dose was considered a no effect level since the observations were considered related to the volume of solution administered At 80 mL kg effects included hyperemia decrease in hemoglobin and hematocrit values decreased serum calcium and uric acid values and increased serum sodium and potassium One animal died following infusion However there were no histopathological changes noted in tissue evaluation Studies in dogs were carried out by the intravenous route of administration for five and 30 days Baxter Report Nos R D 1 101A CC1101A R D 1 101 3 N255 The five day study involved the infusion of a solution of 5 synthetic amino acids SAAS plus 25 dextrose at 100 mL kg day two different groups received 100 mL kg day at 7 5 and 3 mL min and 40 mL kg of the same 5 synthetic amino acid solution plus 5 dextrose At 40 mL kg there was no mortality Clinical observations and increases in serum glucose lactic acid and urea nitrogen and increases in urinary excretion were largely attributed to the volume and quantity of material administered There were no histopathological changes in any tissue However the administration of 100 mL kg resulted in mortality and involved all dogs that received the solution at a rate of 7 5 mL min and some dogs that received 3 mL min The cause of death was attributed to the rapid increase in blood osmolality
37. o Acid Peritoneal Dialysis Solution Page 5 of 31 carefully monitored Patients should be carefully monitored to avoid over and underhydration An accurate fluid balance record must be kept and the body weight of the patient must carefully be monitored Serum electrolyte concentrations particularly bicarbonate potassium magnesium calcium and phosphate blood chemistry including parathyroid hormone and hematological parameters should be evaluated periodically In patients with diabetes blood glucose levels should be monitored and the dosage of insulin or other treatment for hyperglycemia should be adjusted ADVERSE REACTIONS Adverse Drug Reaction Overview The adverse reactions within this section represent those that are thought to have an association with Nutrineal PD4 or in conjunction with performing the peritoneal dialysis procedure Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug Adverse drug reaction information from clinical trials is useful for identifying drug related adverse events and for approximating rates In clinical trials the following Adverse Events were observed in gt 5 of patients receiving Nutrineal PD4 Adverse events are presented in the table if the inciden
38. olyte disturbances may be managed according to the specific electrolyte disturbance verified by blood testing The most probable disturbance hypokalemia may be managed by the oral ingestion of potassium or by the addition of potassium chloride in the peritoneal dialysis solution prescribed by the treating physician ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action Peritoneal dialysis is a procedure which utilizes the body s peritoneal membrane as a natural filter for removing toxic substances and metabolites normally excreted by the kidneys and for aiding in the regulation of fluid electrolyte and acid base balance Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 10 of 31 While in conventional peritoneal dialysis solutions the osmotic agent is dextrose in Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution the osmotic agent is a mixture of essential and nonessential amino acids with a total concentration of 1 1 11 g L Electrolyte concentrations in the dialysis solution have been formulated to normalize plasma electrolyte concentrations lactate is present as a bicarbonate precursor The amino acids in Nutrineal PD4 provide an osmotic gradient similar to peritoneal dialysis solutions with 1 5 dextrose The calculated osmolarity of Nutrineal PD4 is 365 mOsmol L whereas the calculated value for peritoneal dialysis solutions with 1 5 dextrose e g Dianeal PD 2 Peritoneal Dialysis
39. on N Delmore T Detsky AS Whitewell J O Sullivan R Cattran DC Richardson RM Jeejeebhoy KN Nutritional assessment of continuous ambulatory peritoneal dialysis patients ASAIO Trans 1987 Jul Sep 33 3 650 3 Kamin H Handler P The metabolism of parenterally administered amino acids II Urea synthesis J Biol Chem 1951 Jan 188 1 193 205 Quadbeck R F rster H Effects of parenteral administration of high dosed single amino acids in human volunteers and in the experimental animal J Parenter Enteral Nutr 1982 July 6 4 318 Gullino P Winitz M Birnbaum SM et al Studies on the metabolism of Amino Acids and related compounds in vivo 1 Toxicity of essential amino acids individually and in mixtures and the protective effect of L arginine Arch Biochem Biophys 1956 Oct 64 2 319 32 Milne MD Pharmacology of amino acids Clin Pharmacol Ther 1968 Jul Aug 9 4 484 516 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 26 of 31 12 Lewis RJ Sr Tatken RL editors Registry of Toxic Effects of Chemical Substances In U S Department of Health and Human Services DHHS NIOSH Publication No 81 116 Washington D C U S Government Printing Office 1982 13 Greenstein JP Birnbaum SM Winitz M Otey MC Quantitative Nutritional Studies with Water Soluble Chemically Defined Diets I Growth Reproduction and Lactation in Rats Arch Biochem Biophys 1957 Dec 72 7 396 416 14 Rose WC The nutritive sign
40. ose increments which often approximated 50 of the LDso were required for the LDo9 Symptoms of toxicity appeared from 10 minutes to 2 hours after the intraperitoneal injection all amino acids caused dyspnea hypothermia and extreme prostration Body temperature was often reduced to 35 C before death The prostration was usually associated with uncoordinated movements Pathologic changes were most obvious in the kidney and liver The glomeruli were congested and there were degenerative changes and vacuolization in renal tubular and hepatic parenchymal cells The lesions were completely reversible if the animal survived Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 22 of 31 Acute toxicity studies of mixtures of amino acids were also studied extensively The toxicity of mixtures of amino acids is not strictly additive and the LDso of such mixtures is always less than would be calculated from the toxicities of each constituent single amino acid Table 8 Intraperitoneal LD5 Doses of L Amino Acids in Rats Compound LD y mmoles kg body weight LD5 mg kg body weightt L Alanine 37 5078 L Arginine HCl 18 3 3793 L Glycine 471 3528 L Histidine HCl 23 3 3569 L Isoleucine 52 6 6821 L Leucine 41 9 5378 L Lysine HCl 22 4 4019 L Methionine 29 9 4328 L Phenylalanine 32 3 5286 L Proline no data no data L Threonine 26 2 3097 L Tryptophan 8 1 1634 L Tyrosine No data
41. rangible at patient connector Remove pull ring from the patient connector Remove disconnect cap from patient transfer set Immediately attach patient transfer set connector to the patient connector by twisting the connector until firmly secured 10 Clamp new bag solution line 11 Break frangible at container port 12 Hang the new solution container 13 Place the drainage container below the level of the peritoneum CaN Proceed with either Procedure A or Optional Procedure B Procedure A 14 Open transfer set clamp to drain solution from the peritoneal cavity 15 Close transfer set line clamp after drainage is complete 16 Open new solution line clamp and allow the new solution to flow into the drainage container for five seconds 17 Clamp drain line 18 Open transfer set clamp and allow the solution to flow into the peritoneal cavity 19 Close transfer set clamp when infusion is complete 20 Open a new disconnect cap following the directions accompanying the cap Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 29 of 31 21 Disconnect the patient transfer set from the TWIN BAG set and attach the new disconnect cap to the transfer set Optional Procedure B 14 Open new solution line clamp and allow the new solution to flow into the drainage container for five seconds 15 Clamp new solution line 16 Open transfer set clamp to drain solution from the peritoneal cavity
42. symptoms metabolic acidosis nausea and vomiting Particular care is indicated in cases of uncompensated metabolic acidosis severe liver dysfunction and hyperammonemia Metabolic acidosis should be corrected before and during Nutrineal PD4 treatment A portion of the amino acids in Nutrineal PD4 is converted to metabolic nitrogenous waste such as urea If dialysis is insufficient the additional metabolic waste generated by the use of Nutrineal PD4 may lead to the appearance of uremic symptoms such as anorexia or vomiting Symptoms can be managed by discontinuation of Nutrineal PD4 or an increased dialysis dose with a non amino acid based solution Metabolic acidosis may be treated with an oral source of alkali such as sodium bicarbonate calcium carbonate or calcium acetate Sexual Function Reproduction Long term animal studies with Nutrineal PD4 have not been performed to evaluate the effect on fertility Special Populations Pregnant or Nursing Women There are no adequate data from the use of Nutrineal PD4 in pregnant or lactating women Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing Nutrineal PD4 Pediatrics Safety and effectiveness in pediatric patients have not been established Monitoring and Laboratory Tests In patients using cardiac glycosides plasma level of potassium calcium and magnesium must be Nutrineal PD4 1 1 Amin
43. ted with the use of health products to the Canada Vigilance Program by one of the following 3 ways Report online at www healthcanada gc ca medeffect Call toll free at 1 866 234 2345 Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program Health Canada Postal Locator 0701C Ottawa ON K1A 0K9 Postage paid labels Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect Canada Web site at www healthcanada gc ca medeffect NOTE Should you require information related to the management of side effects contact your health professional The Canada Vigilance Program does not provide medical advice MORE INFORMATION This document plus the full product monograph prepared for health professionals can be found at http www baxter ca or by contacting the sponsor Baxter Corporation at 1 800 387 8399 This leaflet was prepared by Baxter Corporation Last revised July 30 2012 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 31 of 31
44. the peritoneum The peritoneum is the membrane surrounding your internal organs such as your intestines and liver The fluids and wastes are removed from your body when the Nutrineal PD4 solution is drained When it should not be used Do not use Nutrineal PD4 If you are allergic to any of the ingredients If your blood urea level is above 38 mmol L If you have uremic symptoms such as loss of appetite nausea or vomiting If you suffer from a disorder affecting amino acid metabolism If you suffer from liver insufficiency If your blood potassium level is too low If you have a disorder called metabolic acidosis If you have a surgically uncorrectable problem affecting your abdominal wall or cavity or uncorrectable problem that increases risk of abdominal infections If you have documented loss of peritoneal function due to severe peritoneal scarring What the medicinal ingredients are Amino Acids Histidine Valine Isoleucine Alanine Leucine Arginine Lysine Glycine Methionine Proline Phenylalanine Serine Threonine Tyrosine Tryptophan Electrolytes Calcium Chloride Dihydrate Magnesium Chloride Hexahydrate Sodium Chloride Sodium Lactate What the nonmedicinal ingredients are Hydrochloric acid for pH adjustment Water for Injection What dosage forms it comes in Nutrineal PD4 is a sterile solution available in TwinBag containers in 2 0 L and 2 5 L sizes and Single Bag containers in 2 5 L s
45. tion Page 2 of 31 NUTRINEAL PD4 1 1 Amino Acid Peritoneal Dialysis Solution PART I HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form Ingredients Administration Strength Intraperitoneal Solution 1 1 Amino Histidine Valine Isoleucine Alanine Leucine Acids Arginine Lysine Glycine Methionine Proline Phenylalanine Serine Threonine Tyrosine Tryptophan Calcium Chloride Dihydrate Magnesium Chloride Hexahydrate Sodium Chloride Sodium Lactate Hydrochloric acid for pH adjustment Water for Injection INDICATIONS AND CLINICAL USE Nutrineal PD4 is indicated for the treatment of protein malnutrition in peritoneal dialysis patients CONTRAINDICATIONS Nutrineal PD4 is contraindicated in patients with e known hypersensitivity to any amino acids in the product or to any of the excipients or components of the container For a complete listing see the Dosage Forms Composition and Packaging section of the product monograph serum urea level above 38 mmol L uremic symptoms metabolic acidosis inborn errors of amino acid metabolism liver insufficiency severe hypokalemia uncorrectable mechanical defects that prevent effective peritoneal dialysis or increase the risk of infection e documented loss of peritoneal function or extensive adhesions that compromise peritoneal function Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 3 of 31
46. tions The dose of 120 mL kg day of 2 amino acid solution with electrolytes can be considered a no effect level Noting that in most cases human exposure is one to two exchanges per day and that clinical usage involves removal of the solution after a prescribed dwell time provides enhanced margins of safety In separate additional studies amino acid solutions were also administered intravenously to rats for five or 30 days Baxter Report Nos R D 01 101 CC1101B R D 1 101A CC1101A In the Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 23 of 31 five day study doses of 40 mL kg of a 3 essential amino acid solution resulted in no significant signs of toxicity or histopathological effects and despite a mild transient hypokinesia this dosage was considered a no effect level The highest dose in this study was initially 120 mL kg which resulted in mortality on the first day A reduction in this dose to 80 mL kg produced signs that were limited to hypokinesia that was more pronounced than that seen at the lower dose but was nevertheless tolerated for the remaining four days The dose of 80 mL kg represents the average blood volume per kg of body weight in mammalian species 1 e this dosage volume results in doubling the total vascular volume by the end of the infusion period In the 30 day intravenous study rats received daily doses of 40 and 80 mL kg of a 5 synthetic amino acid solution SAAS At 40 mL kg sig
47. toneal dialysis solutions The studies reported that amino acids are rapidly absorbed from the peritoneal cavity during dialysis with such a solution and that there is on the average net absorption of 70 90 of the amino acids infused intraperitoneally during a 4 6 hour dwell The acute effect of Nutrineal PD2 on plasma amino acid concentrations was assessed by sampling plasma before and at the end of a four hour morning exchange with Nutrineal PD2 Pre and post exchange plasma amino acid concentrations for Day 16 which was the first day in which patients received Nutrineal PD2 are shown in Table 4 Overall the mean increase in amino acid concentration above pre exchange for the amino acids included in the solution was about 63 at the end of the four hour exchange The increases ranged from 21 for lysine to 196 for methionine The table also includes increases or decreases in concentrations of amino acids that were not present in Nutrineal PD2 Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 18 of 31 Table 4 Pre and Post Exchange Plasma Amino Acid Concentrations Day 16 During Treatment with Nutrineal PD2 Pre Exchange Post Exchange percent p value N 21 Essential Amino Acids Histidine soleucine eucine ysine 160 32 Methionine 24 10 henylalanine 56 17 hreonine 11734 ryptophan E 11 Valine 30 Semi Essential Amino Acids Cystine yrosine Alanine Arginine
48. ts on the peritoneal membrane In an uncontrolled clinical study in an outpatient setting using Nutrineal PD4 with 2 5 mEq L calcium electrolyte concentration Baxter Clinical Study No PRO NIV AO 048C statistically significant increases in serum albumin p lt 0 01 and transferrin p lt 0 05 were observed at month 3 end of treatment In a 35 day controlled metabolic balance study in patients with protein calorie malnutrition Baxter Clinical Study No DT88002 a significant improvement in nitrogen balance occurred during the use of Nutrineal PD2 The significant improvement in nitrogen balance was accompanied by statistically significant increases in serum total protein and serum transferrin increases in serum albumin and a trend toward normalization of plasma amino acids Nutrineal PD4 1 1 Amino Acid Peritoneal Dialysis Solution Page 16 of 31 Significant decreases from baseline were observed for both phosphorus p 0 050 and 0 006 respectively and potassium p 0 045 and 0 031 respectively in the 35 day metabolic balance study and in a controlled three month outpatient study Clinical research has shown that phosphorus and potassium balances usually change in parallel with nitrogen balance In the absence of significant dietary changes serum concentrations of potassium and phosphorus decrease when nitrogen balance increases To evaluate the amount of amino acids taken up from Nutrineal PD2 dialysate amino acid con
49. ueous solution and offered together with a separate supplement of fat soluble vitamins in corn oil to weanling rats At maturity the animals were mated and produced normal litters with no evidence of reduced fertility or embryotoxicity The F1 litters were maintained on the purified amino acid diets and at maturity yielded satisfactory litters F2 generation that were nursed to weaning These studies indicate a purified amino acid diet when supplemented with appropriate vitamins salts fat and carbohydrate does not have adverse effects on reproduction and fetal survival Genotoxicity Studies The components in Nutrineal PD4 have been shown to be nonmutagenic considering that these components are food sources for all living organisms All of the in vitro models for determining mutagenic potential utilize culture media composed of the same purified amino acids contained in this product The amino acids contained in Nutrineal PD4 are highly purified and meet the U S Pharmacopeial standards and are Generally Recognized as Safe GRAS as cited in US 21 CFR Parts 172 and 582 Hence it is unlikely that the product is mutagenic Carcinogenicity Studies Nutrineal PD4 has not been tested for carcinogenic potential in animal species because the route of administration is not practical for long term application in laboratory animals Oral feeding studies of purified diets with other nutrients have not shown evidence of carcinogenicity attributa
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