FUJISAWA's PROGRAF WILL BE AVAILABLE BY EARLY JUNE FOLLOWING APPROVAL FOR LIVER TRANSPLANT REJECTION PREVENTION; POST- TRANSPLANT DOSING MAY BE ADVANTAGE

Fujisawa will begin marketing Prograf to liver transplant centers in early June. The first immunosuppressant for the prevention of organ transplant rejection to be approved in over 10 years, Prograf (tacrolimus/FK506) cleared FDA on April 8 ("The Pink Sheet" April 11, T&G-1).

The company is starting out with a small sales force of 15 reps provided by Deerfield, Ill.-based Immunology Products Specialists to detail Prograf to the 82 liver transplant centers in the U.S. About 3,000 liver transplants are performed in the U.S. annually.

The product will be manufactured at Fujisawa's plant in Killorglin, Ireland using raw material produced in Toyama, Japan. Fujisawa's only U.S. plants, acquired from Lyphomed, are still undergoing FDA review for compliance and fraud problems associated with previous management. FDA has put a hold on reviews of applications of products manufactured at those plants.

FDA continues its effort to reduce approval times for important new therapies under the mandate of the user fee act, clearing Prograf in just over eight months.

Fujisawa submitted NDAs (50-708 and 50-709) for capsule and I.V. formulations in July and August. The drug received a "1P, E" rating, designating a new molecular entity given priority and expedited review.

Prograf is indicated "for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants," to be used concomitantly with adrenal corticosteroids. Prograf injection "should be reserved for patients unable to take Prograf capsules orally," labeling states.

Labeling notes that in clinical studies "the Prograf-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens."

FDA's Antiviral Drugs Advisory Committee Subcommittee on Immunosuppressants unanimously agreed at its Nov. 22, 1993 meeting that Prograf performed as well as Sandoz' Sandimmune (cyclosporine) and was not superior in efficacy in the primary endpoint of one-year survival and one-year graft survival ("The Pink Sheet" Nov. 29, 1993, p. 5). Sandimmune is approved for prophylaxis of organ rejection in kidney, liver and heart transplants.

In clinical trials involving 529 liver transplant patients in the U.S. and 545 in Europe, overall one-year survival for Prograf patients was 88% and 78%, respectively. The rate of one-year graft survival for Prograf in the U.S. study was 81% and 73% in the European study.

Labeling notes that information on secondary outcomes, such as incidence of acute rejection, use of Ortho's Orthoclone OKT3 for steroid-resistant rejection, and incidence of refractory rejection was collected in the clinical trials. However, "because of the nature of the study designs, comparisons of difference between the study arms for these secondary endpoints could not be reliably assessed."

The antivirals advisory subcommittee voted unanimously that Prograf has not been demonstrated to be superior to cyclosporine with respect to secondary endpoints after considering data presented by Fujisawa that showed a trend in Prograf's favor for acute rejection rates of 68% versus 76% for cyclosporine. The company also reported that one-year refractory rejection for Prograf was 3% compared to 15% for cyclosporine. Committee member Donald Hricik, MD, University Hospitals of Cleveland, remarked that the open-label design of the studies increased the likelihood of bias in interpreting the results.

Prograf will be available in 1 mg and 5 mg capsules containing anhydrous tacrolimus, and 5 mg/ml castor oil and alcohol solution for injection. Prograf is administered "no sooner than six hours" after transplantation. The dose for injection is .05-.10 mg/kg/day. "Continuous intravenous infusion of Prograf injection should be continued only until the patient can tolerate oral administration of Prograf capsules," labeling states, because of a risk of anaphylactic reaction to the castor oil in the injectable form.

The dose for oral administration is .15-.30 mg/kg/day at 12 hour intervals. The transition to oral dosing "usually occurs within two to three days," labeling states. The first dose of oral therapy is recommended to be given eight to 12 hours after discontinuing the I.V. infusion. Labeling recommends that adult patients receive doses at the lower end of the dosing range while pediatric patients may require higher doses in the .1 mg/kg/day range for intravenous and .3 mg/kg/day for oral Prograf.

One feature that may distinguish Prograf is the ability to initiate therapy with an oral dose post-transplant. Sandimmune therapy is initiated four to 12 hours prior to transplantation, often intravenously, to maintain levels of the drug in the blood.

At the FDA advisory committee meeting, committee member Lawrence Hunsicker, MD, University of Iowa, commented: "There are differences that I think are, in fact, demonstrable between the drugs and we shouldn't, in our rush to say that they're totally "Tweedledee and Tweedledum," ignore the differences that are ascertainable." Hunsicker referred specifically to the "ability to give [Prograf] orally shortly after transplantation" as a "substantial advantage."

Hunsicker said: "I, like some of my brethren here, have had the opportunity to try to manage liver patients following liver transplants when they're draining bile, and one really is required to use intravenous cyclosporine to maintain adequate levels, and this does put the patient at some risk for toxicity."

Sandimmune labeling carries a boxed warning that recommends patients be monitored at repeated intervals for cyclosporine blood levels and dosing be adjusted in patients taking soft gelatin capsules or oral solution because of the "erratic" absorption of those cyclosporine formulations during chronic administration.

* Prograf does not carry a similar boxed warning; however, labeling calls absorption after oral administration "variable." In addition, the Prograf labeling includes a section on "blood concentration monitoring" under dosage and administration, advising that "most study centers have found tacrolimus blood concentration monitoring to be helpful in patient management." Labeling adds that "while no fixed relationship has been established, such blood monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance."

Similar to Sandimmune, Prograf labeling bears a boxed warning concerning the risk of developing lymphoma associated with immunosuppressive agents. Both agents are associated with nephrotoxicity, but unlike Sandimmune, Prograf therapy has been associated with mild to severe hyperkalemia in 44% of U.S. patients and neurotoxicities that include tremor, headache, and changes in motor function, mental status and sensory function in 55% of patients, as well as hyperglycemia in about 47% of the patients in clinical trials. Prograf lacks the Sandimmune side effect of hirsutism, which is of concern particularly in children.

In FDA's approval letter for the product, the agency reminds Fujisawa that the company has committed to conducting several Phase IV studies, including "additional clinical, pharmacology/toxicology, and pharmacokinetic studies; collection of certain data; and development of a new dosage form."

The advisory committee expressed interest in seeing further pharmacokinetic studies conducted in children as well as adults. Committee members suggested that Fujisawa develop a Prograf oral solution and other dosage strengths that would be bioequivalent, since the 1 mg and 5 mg capsules are bioinequivalent.

Drug interactions also were a concern of the committee, which recommended that studies be done with fluconazole, erythromycin, phenytoin and diltiazem. Prograf labeling notes that drug interaction studies have not been done but lists 20 drugs with which tacrolimus may interact because of its metabolism through cytochrome P-450 HIA enzyme systems. Fujisawa is conducting clinical trials with Prograf for the indications of scleroderma, rheumatoid arthritis, lupus and polymyositis.