DEPARTMENT OF PHARMACY SERVICES – DRUG INFORMATION …

UNIVERSITY HEALTH NETWORK (UHN) ?

TORONTO GENERAL HOSPITAL/TORONTO WESTERN HOSPITAL/PRINCESS MARGARET HOSPITAL

DEPARTMENT OF PHARMACY SERVICES ? DRUG INFORMATION SERVICE

CANADIAN MALARIA NETWORK ? DISTRIBUTION OF ARTESUNATE AND QUININE: GUIDELINES FOR PHARMACY STAFF

BACKGROUND: The Canadian Malaria Network (CMN) in collaboration with Health Canada's Special Access Programme and the Public Health Agency of Canada, maintain supplies of intravenous (IV) artesunate and quinine at major medical centres across the country to facilitate rapid 24-hour access to effective treatment of severe acute malaria. The UHN and Toronto General Hospital (TGH) in particular are one of the distributions centres for these two antimalarial drugs. As of June 2009, the Pharmacy at TGH has a supply of both artesunate and quinine injection.

CHOICE OF AGENT: Artesunate: This new agent is now considered first-line treatment of severe malaria in all patients with the exception of women during the first trimester of pregnancy. However, if quinine injection is not readily available or the patient cannot tolerate quinine, then the benefit of artesunate in the first trimester outweighs the risk of inadequate treatment of severe malaria to both the mother and fetus. Artesunate IV injection offers more rapid clearance of parasites, reduced mortality, better tolerated and easier to administer than IV quinine. The artesunate injection currently supplied is under clinical investigation by the U.S. Army's, Walter Reed Institute of Research and is the same product supplied by the U.S. Centers for Disease Control. The product is subject to Good Manufacturing Practices. It exhibits efficacy and safety similar to the formulation used in published clinical trials. Quinine: The role of this agent is now limited to the treatment of severe malaria in women during the first trimester of pregnancy and when artesunate is not readily available or the patient cannot tolerate artesunate.

DISPENSING: UHN-Treated Patients: All physicians at UHN may prescribe/order artesunate or quinine injection under the CMN program. The physician or the pharmacist does not have to contact the Special Access Programme each time one of these drugs is requested. The selection of the appropriate agent is the responsibility of the prescribing physician. However, the prescriber should be notified that two different agents are available along with the decision-making process regarding the choice of agent before dispensing the medication. You may refer the prescribing physician to the revised guidelines for "Treatment of Malaria" listed in the UHN Intranet version of the 2009 edition of the Guidelines for Antimicrobial Use ("Antibiotic Handbook") located on the Pharmacy Web Page. Pharmacy will supply the same pre-packaged kit of information and antimalarial drug as provided for outside hospitals (see "Requests From Outside Hospitals"). For on-call Pharmacists, a small supply of artesunate and quinine injection is available in the night cupboard, Gerrard Wing, GW-ground 510, TGH for first doses. Note: Artesunate is stored in refrigerator.

Requests From Other Hospitals: During usual working hours, the Senior Staff Technician or In-Patient Pharmacists at TGH will handle requests from other hospitals. After hours, the on-call Pharmacist at TGH will handle the requests. The requesting hospital should make arrangement to pick-up and deliver the required agent. Artesunate and phosphate buffer located in the walk-in fridge ?instruction for preparing a kit provided) Note: For artesunate, package supply in an insulated container (e.g., Styrofoam box with lid) with cold packs (located in Sterile Products area in small freezer under counter) to keep under refrigeration during shipping. Stock supply located in the walk-in refrigerator. Quinine kits are located in Sterile Products Area.

The selection of the appropriate antimalarial is the responsibility of the prescribing physician. However, as noted above, the hospital making the request should be notified of the existence of two agents and the selection process. A packet of information supplied at the time of dispensing includes:

? Introduction to the Canadian Malaria Network ? Introducing ARTESUNATE ? Summary Information sheets for artesunate and quinine injection ? Guidelines for the Treatment of Malaria ? Form A: Parenteral Therapy for Severe Malaria (to be completed by attending physician and returned to

CMN Coordinating Centre within 48 hours of request ? Form B: Parenteral Therapy for Severe Malaria (to be completed by attending physician and returned to the

CMN Coordinating Centre at patient discharge or end of malaria treatment

Quantity To Dispense: Since both artesunate (4-dose supply) and quinine injection dosage regimens are weightbased the following is provided as a guide. Artesunate: 42 kg or less = 4 vials; 43 kg to 85 kg = 8 vials; greater than 85 kg to 125 kg = 12 vials;

Note - with each vial of artesunate supply one vial of phosphate buffer diluent

Quinine Dihydrochloride: prefilled standard kits contain 7 ampoules

SPECIFIC INFORMATION FOR EACH ANTIMALARIAL AGENT

Artesunate

Dosage Form: Two components, single-dose vial contains 110 mg as a sterile dry-filled powder and a single-dose vial containing 12 mL of sterile 0.3 M, pH 8.1 phosphate buffer solution as a diluent.

Preparation: Pharmacy is not able to provide an IV additive service for artesunate injection. Staff on the nursing unit will use the following procedure using aseptic technique. Withdraw 11 mL of phosphate buffer diluent into a 30 mL syringe and inject slowly into each artesunate vial (against the wall). Gently swirl the vial for 5 to 6 minutes to provide a clear colourless 10 mg per mL solution in a total volume of 11 mL. Repeat this procedure if a second vial is required (patients more than 42 kg). After mixing, use the drug within one hour. Discard any unused solution. Using the same syringe, withdraw the required dose from the artesunate vial(s). At least 10 mL (100 mg) can be easily withdrawn from each vial. Remove the needle from the syringe and attach a 0.8 micron hydrophilic polyethersulfone syringe filter (e.g., PharmAssure?, Supor membrane). Attach a new sterile needle to filter/syringe. If a suitable syringe filter is not available, do not delay in administering any dose of artesunate. A syringe filter is preferred but is not mandatory.

Dosage & Administration: 4-dose regimen as follows ? 2.4 mg per kg IV at 0, 12, 24, and 48 hours (total dose is 9.6 mg per kg). Each dose is administered direct IV push over 1 to 2 minutes into an established IV line of either D5W or Normal Saline. Administer the first dose STAT. Only physicians may administer artesunate IV at UHN.

Storage & Stability: Dry Powder: Store refrigerated at 2 to 100C; if inadvertently left at room temperature (15 to 300C) for several days, the drug is still active and may be used. The current product has no expiry date. It was manufactured in September/October 2004 for use in clinical trials and is subject to ongoing retesting every 3 months.

Phosphate Diluent: Usually stored refrigerated along with the artesunate powder. However, the diluent is stable when stored a room temperature (15 to 300C). If the phosphate buffer forms crystals or precipitate when stored under refrigeration, the vials may be warmed by rolling the vial between one's hand or allow the vials to stand in a warm place (15 to 300C) until the crystals dissolve resulting in a clear and colourless solution. If the solution remains cloudy, crystals are still present or the solution is coloured, discard the vial.

Reconstituted Solution: Once artesunate is dissolved in the phosphate buffer diluent, use within one hour of preparation. Discard any unused solution.

Quinine Dihydrochloride

Dosage Form: 600 mg per 2 mL ampoule (300 mg per mL) sterile solution

Preparation: Pharmacy is not able to provide IV additive service for quinine injection. Staff on the nursing unit will use the following procedure using aseptic technique. Crack open the required number of ampoules for the dose and withdraw contents into a syringe. Inject dose of quinine into an IV bag. For loading dose using an IV pump, dilute dose in 100 mL. For loading dose not using an IV pump and for maintenance doses, dilute in 500 mL (or a volume of 10 mL per kg patient's bodyweight).

Dosage & Administration: All dosages are listed as quinine dihydrochloride salt Loading Dose: 20 mg per kg infused over 4 hours in 500 mL (or 10 mL per kg bodyweight); if a more rapid loading dose is used in life-threatening situations, then at UHN a physician must administer the dose as 7 mg per kg infused over 30 minutes in 100 mL followed immediately by 10 mg per kg in 500 mL (or 10 mL per kg bodyweight) infused over 4 hours.

Notes: ? For the 30-minute infusion, a volumetric pump must control infusion rate. ? Nurses at UHN are only authorized to administer 4-hour infusions

Maintenance Doses: Eight hours after completion of loading dose, start first maintenance dose of 10 mg per kg. Repeat maintenance dose every 8 hours. Each maintenance dose is diluted in 500 mL (or 10 mL per kg bodyweight) and is infused over 4 hours. Volumetric pumps may be used but are not mandatory for 4-hour infusions of quinine.

Storage & Stability: Concentrated Solution: Store a below 250C, protected from light until expiry date on each ampoule. Once ampoule opened, discard any unused portion. Infusion Solution: May dilute in D5W or Normal Saline and use immediately after preparation.

Prepared by: John Murdoch, B.Sc.Phm.

Date: June 24, 2009

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