……………For Your Drug Information ………….

1). Remodulin® (treprostil sodium) - a synthetic form of prostacyclin used in the treatment of pulmonary hypertension. Compared to Flolan® (epoprostenol), this new product is designed for subcutaneous delivery via a small infusion pump. (see Drugs in Review)

2). Bravelle® (urofollitropin) - a human-derived follicle stimulation hormone (FSH) for induction of ovulation.

3). Neulasta® (pegfilgratim) - a colony stimulating factor (GCSF) used to reduce the incidence of infection in non-myeloid cancer patients with chemotherapy induced immune suppression. The dose is 6 mg subcutaneously, once per chemotherapy cyle. Do not use in the 14 day period prior to chemotherapy or the 24 hour period after chemotherapy has been administered.

4). Vfend® (voriconazole) - this lipohilic azole anti-fungal is available in oral and intravenous form for the primary treatment of acute invasive aspergillosis and as salvage therapy for rare, serious fungal infections due to Scedosporium apiospermum and Fusarium spp. (see Drugs in Review.)

1). Changes in blood glucose with Tequin®: Cases of serious hyper- and hypoglycemia have been reported to the FDA in patients taking Tequin®, primarily in patients with type 2 diabetes. Several of the patients in the case reports included patients who were concomitantly being treated with oral hypoglycemic agents. The company has revised the WARNINGS section of their package insert to reflect these new findings. The hypoglycemic episodes were generally seen within the first 3 days of therapy. The hyperglycemic episodes occurred between 4 and 10 days after initiation of Tequin® therapy. The alterations of blood sugars in the above patient population can be severe and life threatening. Other patient populations that may be at increased risk include those >75 years with unrecognized diabetes, age-related decrease in renal function, or on other medications that can cause hyperglycemia. Careful monitoring of blood glucose in the above patient populations is recommended, if Tequin® therapy is initiated. If hyper- or hypoglycemia occur while taking Tequin®, alternative antibiotic therapy may be necessary.

2). Black box warning and intrathecal Lioresal® (baclofen) withdrawal syndrome: Baclofen is FDA approved for intrathecal administration in the management of severe spasticity of cerebral and spinal origin. The black box warning pertains to abrupt withdrawal of baclofen resulting in a severe, life-threatening withdrawal syndrome.

3.) Black box warning and Dear Doctor Letter for Nolvadex (tamoxafen) – AstraZeneca issued a Dear Doctor letter for the additional black box warning added to the package insert. It states - "While it has been known that Nolvadex treatment is associated with an increased risk of endometrial cancer, recent information indicates that there is also an increased risk of developing a rare and more aggressive uterine sarcoma. These data, and the previously reported increased risk of stroke and pulmonary embolism, have prompted changes to the Nolvadex label." The letter stresses that the physician need to discuss these risks and known benefits of this drug with the patient.

Drugs classes such as angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs can augment the renal injury that may result from anesthetic induced hypotension or intraoperative blood loss.

Withdrawal effects can be seen from other classes of drugs such as beta blockers, centrally acting sympatholytics, benzodiazepines, and opoid analgesics. If the patient is unable to oral medications for an extended period other routes for delivering these types or medications should be explored.

This table covers some of the major drug classes that patient’s often come into the hospital on but a more extensive list can be found in the reference listed below. The article is filed in the Drug Information files under "Surgery".

Spell NO. Stopping and Restarting Medications in the Perioperative Period. Medical Clinics of North America. September 2001 Vol.85(5).

Jabbour SA. Steroids in the Surgical Patient. Medical Clinics of North America, September 2001 Vol.85(5), pp.1311-1317.

A press release from Abbott Laboratories dated February 14, 2002 stated that new safety data suggests that Depacon® infused over five to ten minutes at rates up to 3 mg/kg/min and doses up to 15 mg/kg is generally well tolerated by patients. This information is based on a safety study conducted in 112 patients with epilepsy by Abbott Laboratories.

The Child-Pugh Scoring System is a scoring system designed by RNH Pugh et al ( Brit J. Surgery.60:646-54.1973). It has since been used to evaluate prognosis in liver cirrhosis/ chronic liver disease. The scoring system has also been used, along with other guidelines, for adult placement on the liver transplant list. Since there is really no reliable measuring tool to assess hepatic function and drug metabolism, this serves as a guide to assess some new drugs that have dosing recommendations based on this scoring system. It is at best a "logical guestimate" and applies only to drugs with dosing recommendations for this scoring system.

Grading system for cirrhosis: The Child – Pugh score

Child Class B: Indicated for liver transplant evaluation; Abdominal surgery peri-operative mortality:30%

Child Class C: Life expectancy 1-3 yrs; Abdominal surgery peri-operative mortality:82%

Reference:

Pugh RNH et al. Transection of the esophagus for bleeding esophageal varices. Brit J Surg.60:646-54.1974

Luccy MR, et al. Minimal criteria for placement of adults on the liver transplant waiting list. Liver Transplantation and Surgery.3(6). 628-637.1997

Riley TR et al. Preventative Strategies in chronic liver disease: Part II:Cirrhosis. Am Fam Physician 64(10):1735-40.2001.

VfendÒ is available in both IV and tablet form with the oral form having ~ 96% bioavailability. It undergoes extensive tissue distribution and ~ 58% protein bound which is unaffected by either hepatic or renal insufficiency. VfendÒ is metabolized by the CYP450 enzymes (CYP2C19, CYP2C9, and CYP3A4) thus has several significant drug interactions to consider (see drug interaction table). It follows non-linear pharmacokinetics.

Dosage adjustment for oral voriconazole is not needed for renal failure but it is recommended to give half the standard dose if patient has mild to moderate liver failure (Child-Pugh Class A and B). Not been studied in patients with severe liver impairment.

IV voriconazole should not be administered to patients with moderate-severe renal impairment (CrCl < 50ml/min) due to accumulation of IV vehicle (SBECD = sulfa butyl ethyl beta cyclodextran).

Age and gender does not affect dosing regimen. Not approved for children <12y/o (dosing information available in clinical trials – see files).

Oral tablets must be taken 1 hour prior to and 1hour after a meal. IV solution must be diluted to 5mg/ml or less and infused over 1-2 hrs ( 3mg/kg/hr).

Rash( 6%) – mild to moderate severity with some cases of photosensitivity (usually related to long-term use).

Clinically significant increased liver enzymes (13.4%) - usually associated with higher drug levels/doses. Usually resolves with or without dose adjustment or after treatment discontinuation.

Contraindications: See drug interactions for specific drugs. Allergic reaction to voriconazole. No known information regarding cross-sensitivity between voriconazole and other azole antifungals (Caution should be used).

Pregnancy Category:D ( shown to be a teratogen in rats ). Avoid in pregnant women.

Market Availability: Not available until "midsummer".

Reference: Vfend (voriconazole) package insert 2002.

RemodulinÒ (treprostinil sodium) is a new prostacyclin analogue approved for the treatment of pulmonary arterial hypertension in patients with NYHA class II – IV symptoms. Treprostinil has direct vasodilation effect of the pulmonary and systemic arterial vascular beds and direct inhibition of platelet aggregation. It is chemically stable at room temperature and neutral pH and has a longer half-life (2-4hrs) compared to epoprostenol (FlolanÒ ). It exhibits 100% absorption when administered subcutaneously with steady state concentrations occurring in ~ 10hrs. It is extensively metabolized to metabolites with unknown activity. Treprostinil’s effect on certain liver enzymes does not appear inhibitory but it is unknown whether it is an inducer.

Treprostinil is indicated for subcutaneous administration only.

Dosage and administration: Available in 20ml ready-to-use vials of 1mg/ml, 2.5mg/ml , 5mg/ml and 10mg/ml concentrations. Initial doses start at 1.25 ng/kg/min (nanograms per kilogram per minute) and may be adjusted based on improvement of PAH symptoms with minimal side-effects. Doses should be adjusted at no more than 1.25 ng/kg/min increments per week for the first 4 weeks and no more than 2.5 ng/kg/min per week for the remaining duration of infusion. Abrupt cessation of infusion should be avoided due to rebound worsening of PAH.

Adverse effects: Infusion site pain, most common side-effect, which can be mild to severe (leading to drug discontinuation), and may be related to infusion rate. It may improve after several months of treatment and could be minimized by rotating the infusion site every 3 days as opposed to everyday.

Dose related/ limiting effects : Jaw pain, lower limb edema, flushing, headache, hypotension, nausea, vomiting, and diarrhea.

Availability and Pricing: Immediately available from United Therapeutics’ U.S. distributors (Priority Healthcare Corporation and Gentiva Health Services). Tentative pricing ~ $65 per milligram.

Reference:

United Therapeutics FDA letter of approval.

FDA Product information : Remodulin

Simonneau G, Barst RJ, Nazzareno G, et al. Am J Respir Crit Care Me.165(6):800-4. March 2002

Vachiery JL, Hill N, Zwicke D, et al. Chest. 121(5).1561-5. May 2002.

Argis Study Apollo Study

RELAX Study AT3 ECMO Study

Baxter r-AHF-PFM Study

CancerVax Melanoma Study

Cardiology – Fenoldopam Study

Covance (diabetic foot) Study

DCVax – Prostate Cancer Study

DTI – 0009 Study

Exclaim Study

Fusion I (natreccor) Study

ISO Study (UICOMP opoid study)

Synergy Study

Dr. Wang’s heparin/reopro Stroke Study

Voriconazole Study (compassionate use)