Physioneal 40 Glucose 1.36% Clear-Flex Product Monograph

PHYSIONEAL 40 is indicated for:

• Peritoneal dialysis for the treatment of acute and chronic renal failure with manifestations of severe water retention and severe electrolyte imbalance.
• Intoxication with dialyzable substances where adequate alternate treatments are not available.

Bicarbonate/lactate based PHYSIONEAL 40 peritoneal dialysis solutions with a physiological pH are particularly indicated in patients in whom solutions based on lactate buffer only, with a low pH, cause abdominal inflow pain or discomfort.

• PHYSIONEAL 40 is intended for intraperitoneal administration only. Not for intravenous administration.

• Peritoneal dialysis solutions may be warmed 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.

• After removal of the overpouch, immediately open the long-seal (interchamber seal) to mix the two solutions and then open the short SafetyMoon seal (access seal) to allow administration of the mixed solution. The intraperitoneal solution must be infused within 24 hours after mixing.

• PHYSIONEAL 40 should be administered at a rate that is comfortable for the patient. The volume administered is determined by the prescribing physician.

• To avoid the risk of severe dehydration, hypovolaemia and to minimise the loss of proteins, it is advisable to select the peritoneal dialysis solution with the lowest level of osmolarity consistent with fluid removal requirements for each exchange. PHYSIONEAL 3.86% glucose-containing solution is a high osmotic pressure fluid and using it for all exchanges may cause dehydration. (See section WARNINGS AND PRECAUTIONS)

• Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24 hours) (Ronco et al. 2000; Keshaviah et al. 1994). Patients on automated peritoneal dialysis (APD) typically perform 3-5 cycles at night and up to 2 cycles during the day (Blake et al. 1996; Blake et al. 2011). It has been reported in literature that, the fill volume per exchange depends on body size, usually from 2.0 to 2.5 liters per 1.73 m² (Ronco et al. 2000; Keshaviah et al. 1994).

• Aseptic technique should be employed throughout the peritoneal dialysis procedure.

• Do not administer if the solution is discoloured, cloudy, contains particulate matter, shows evidence of leakage between chambers or to the exterior, 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.

• Discard any unused remaining solution.

• For single use only

Pediatrics

• Safety and effectiveness in pediatric patients has not been established. Therefore the clinical benefits of PHYSIONEAL 40 have to be balanced versus the risk of side effects in this patient category.
• For pediatric patients >2 years old, 800 to 1400 mL/m² per cycle up to a maximum amount of 2000 mL, as tolerated is recommended.

Geriatrics

More than 30% of the patients in the clinical trials were older than 65. The evaluation of the results obtained for this group does not show any difference to the rest of the patients.

PHYSIONEAL 40 is contraindicated for use in patients with:

• Uncorrectable mechanical defects that prevent effective PD or increase the risk of infection
• Documented loss of peritoneal function or extensive adhesions that compromise peritoneal function
• Severe respiratory insufficiency • Malnutrition • Severe disorders of lipid metabolism • Pregnancy, unless under the close supervision of a doctor

• 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 PHYSIONEAL 40.

• 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) when possible. Prior to identification of the involved organism(s), broad spectrum antibiotics may be indicated.

• Solutions containing dextrose should be used with caution in patients with a known allergy to corn or corn products. Hypersensitivity reactions such as those due to a corn starch allergy, including anaphylactic/anaphylactoid reactions, may occur. Stop the infusion immediately and drain the solution from the peritoneal cavity if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated.

• Patients with elevated lactate levels should use lactate-containing peritoneal

  dialysis solutions with caution. It is recommended that patients with conditions known to increase the risk of lactic acidosis [e.g., severe hypotension or sepsis, hepatic failure and/or renal failure, inborn errors of metabolism, treatment with drugs such as metformin and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] must be monitored for occurrence of lactic acidosis before the start of treatment and during treatment with lactate-based peritoneal dialysis solutions.

• When prescribing the solution to be used for an individual patient, consideration should be given to the potential interaction between the dialysis treatment and therapy directed at other existing illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac glycosides.

• Diabetics require careful monitoring of blood-glucose levels during and following dialysis with glucose-containing solutions. Dosage of insulin or other treatments for hyperglycemia should be adjusted.

• The use of PHYSIONEAL 40 in the CLEAR-FLEX container is not recommended in patients requiring a fill volume < 1600 mL due to the risk of undetected misinfusion (administration of the buffer chamber only).
• This product may contain fructose as an impurity in the dextrose material. Exercise caution when this product is used in patients with hereditary fructose intolerance. In these patients, fructose may result in hypoglycemia, metabolic acidosis, liver toxicity which manifests as vomiting, nausea, sweating, jaundice, hemorrhage, seizures or coma or even death. The severity of the reactions is dependent on the amount and duration of fructose intake.

• PHYSIONEAL 40 is intended for intraperitoneal administration only. Not for intravenous administration.

• Do not administer if the solution is discoloured, cloudy, contains particulate matter, shows evidence of leakage between chambers or to the exterior, 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.

• Safety and effectiveness in pediatric patients has not been established.

• In patients with plasma bicarbonate level above 30 mmol/l, the risk of possible metabolic alkalosis should be weighed against the benefits of treatment with this product.

• Protein, amino acids, water soluble vitamins and other medicines may be lost during peritoneal dialysis and may require replacement.

• An accurate fluid balance record must be kept and the body weight of the patient should carefully be monitored to avoid over- or underhydration with severe consequences

• Peritoneal dialysis should be done with caution in patients with: 1) abdominal conditions, including disruption of the peritoneal membrane and diaphragm by surgery, from congenital anomalies or trauma until healing is complete, abdominal tumors, abdominal wall infection, hernias, fecal fistula, 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 (Misra et al. 1998) and severe pulmonary disease. When assessing peritoneal dialysis as the mode of therapy in these situations, the benefits to the patient must be weighed against the possible complications.

• Over infusion of PHYSIONEAL 40 solutions into the peritoneal cavity may be characterized by abdominal distension/abdominal pain and/or shortness of breath.

• Treatment of PHYSIONEAL 40 overinfusion is to drain the solution from the peritoneal cavity.

• Excessive use of PHYSIONEAL 40 peritoneal dialysis solution with a higher dextrose (glucose) during a peritoneal dialysis treatment may result in excessive removal of water from the patient.

• Potassium is omitted from PHYSIONEAL 40 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.

• Serum electrolyte concentrations (particularly bicarbonate, potassium, magnesium, calcium and phosphate), blood chemistry (including parathyroid hormone and lipid parameters) and haematological parameters should be evaluated periodically.

• In patients with secondary hyperparathyroidism, the benefits and risks of the use of dialysis solution with a low calcium content such as PHYSIONEAL 40 should be carefully considered as it might worsen hyperparathyroidism.

• Patients must be instructed to open both the long and the short seals prior to infusion. If only the short-seal opens, infusion of the unmixed solution can cause abdominal pain, hypernatremia and severe metabolic alkalosis. In case of infusion of unmixed solution, the patient should immediately drain the solution and use a newly mixed bag.
• Improper clamping or priming sequence may result in infusion of air into the peritoneal cavity, which may result in abdominal pain and/or peritonitis.

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.

The adverse reactions within this section represent those reported in clinical trials involving PHYSIONEAL 35 and PHYSIONEAL 40. In clinical trials with PHYSIONEAL 40 alkalosis occurred in approximately 10% of patients. Alkalosis was not observed in clinical trials with PHYSIONEAL 35.

1. a) Frequency has been evaluated using the following criteria: very common (>1/10), common (≥1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000).
2. b) Reported in PHYSIONEAL 40 only (N=4/46)
3. c) MedDRA LLT (lower level term) = lack of ultrafiltration; PT (preferred term) = peritoneal membrane failure; HLT (high level term) = peritoneal and retroperitoneal disorders; HLGT (high level group term) = peritoneal and retroperitoneal conditions; SOC = gastrointestinal disorders.

Adverse Reactions: General

Adverse reactions to peritoneal dialysis include mechanical and solution related problems as well as the results of contamination of equipment or improper technique in catheter placement.

Post-Marketing Adverse Reactions

In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience. These reactions are listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity.

INFECTIONS AND INFESTATIONS: Peritonitis bacterial, Catheter site infection

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Eosinophilia

GASTROINTESTINAL DISORDERS: Encapsulating peritoneal sclerosis, Peritoneal cloudy effluent, Abdominal discomfort

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Rash

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: Musculoskeletal pain

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Catheter related complication, Pyrexia

Examples of peritoneal dialysis therapy related class effects include: bleeding, ileus, tiredness, muscle cramping

Management of overdose:

• Hypervolemia may be managed by using hypertonic peritoneal dialysis solutions and fluid restriction. Hypovolemia may be managed by fluid replacement either orally or intravenously, depending on the degree of dehydration.
• Electrolyte disturbances may be managed according to the specific electrolyte disturbance verified by blood test. 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.
• Hyperglycemia in diabetic patients may be managed by adjusting the insulin dose.

List of excipients

Hydrochloric acid concentrated (pH adjuster)

Sodium hydroxide (pH adjuster)

Water for Injection

Shelf life after mixing

The product, once removed from its overpouch and mixed, should be used within 24 hours.

• In the case of damage, the container should be discarded.

• Aseptic technique should be employed throughout the peritoneal dialysis procedure.

• Peritoneal dialysis solutions may be warmed 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.

• Drugs should be added through the medication port in the glucose chamber before opening the interchamber peelable seal. The product should be used immediately after any drug addition.

• The pH and salts of the solution must be taken into account for compatibility before adding drug(s) to the solution.

• After removal of the overpouch, immediately open the long-seal (interchamber seal) to mix the two solutions and then open the short-seal (access seal) to allow administration of the mixed solution. The solution should be infused within 24 hours after mixing.

• Discard any unused remaining solution.

• For single use only

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9. 9. Voges M, Faict D, Lechien G, Taminne M. Stability of drug additives in peritoneal dialysis solutions in a new container. Perit Dial Int 2004;24:590-595
10. 10. Voges M, Divino-Filho JC, Faict D, Somers F, Vermeulen P. Compatibility of insulin over 24 hours in standard and bicarbonate-based peritoneal dialysis solutions contained in bags made of different materials. Perit Dial Int 2006; 26:498-502