Section: NEW DRUG APPOVALS, dosage forms, and other product;

PIPELINE PREVIEW

The following agents are nearing FDA approval.

Donepezil HCl (Aricept, Eisai) is approvable for mild to moderate Alzheimer’s disease.

Betaxolol/pilocarpine ophthalmic solution (Betoptic Pilo, Alcon Labs) has ben deemed approvable for the management of glaucoma.

Valproate sodium (Depacon, Abbott Laboratories) has been given approvable status for complex absence seizures, and as adjunct therapy for multiple seizure types.

A call lung surfactant extract (Infasurf, Forest Laboratories) has been declared approvable for prophylaxis and treatment of respiratory distress syndrome in premature infants.

Etodolac (Lodine XL, Wyeth-Ayerst) has received approvable status as an extended release nonsteroidal anti-inflammatory drug.

A gel formulation of ciclopirox (Loprox, Hoechst Marion Roussel) has received approvable status. The broad spectrum antifungal is currently available in cream and lotion formulations.

Ropivacaine HCl (Naropin, Astra), an injectable amide local anesthetic, has been declared approvable for obstetric procedures and postoperative pain management.

Mitoxantrone (Novantrone, Immunex Corporation) has been recommended for approval for late-stage, hormone-resistant prostate cancer therapy.

Danaparoid sodium injection (Orgaran, Organon) has gained approvable status for the prevention of deep vein thrombosis in elective hip surgery.

Mifepristone (RU-486), in combination with misoprostol, has received approvable status for medical termination of interuterine pregnancy.

Sterile aerosol luzenac talc (Sclerosol, Bryan) has gained an approvable status for the treatment of malignant pleural effusion.

Sertindole (Serlect, abbott Labs) has been recommended for approval for the treatment of schizophrenia.

Itraconazole (Sporanox, Jansen Pharmaceutica) is approvable for the treatment of dermatophyte skin infections in patients unresponsive to or unable to take topical therapy.

Mangafodipir trisodium IV (Teslascan, Nycomed) has received approvable status as a liver-specific magnetic resonance imaging contrast agent.

Olanzapine (Zyprexa, Eli Lilly) has been deemed approvable of the treatment of patients with schizophrenia.
NEW MOLECULAR ENTITIES

• ALLEGRA. A nonsedating antihistamine, fexofenadine HCI (Allegra, Hoechst Marion Roussel) has gained FDA approval for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 12 years of age and older.

The precautions section of labeling states that administration of fexofenadine (120 mg q12h) either alone or in combination with ketoconazole (400 mg once daily) orerythromycin (500 mg q8h) produced no differences in adverse effects or QTc intervals; however, it notes that the drug has not been studied in combination with other azole antifungal or macrolide drugs. Also, labeling states that the concomitant administration of fexofenadine with each of these two drugs did increase its peak plasma concentrations and extent of systemic exposure but that these changes were within the ranges seen in well-controlled clinical trials.

Fexofenadine was approved after it was shown in three, 2-week, placebo-controlled trials (1,634patients with seasonal allergic rhinitis between the ages of 12 and 68 years) to significantly reduce total symptom (sneezing; rhinorrhea; itchy, nose, palate, throat; itchy, watery, red eyes) scores after the first 60-mg dose.

The recommended dose is one 60 mg capsule twice daily, with a 60-mg once-daily dose recommended initially for patients with impaired renal function.

The most frequently occurring adverse events in patients treated with fexofenadine during clinical studies were viral infection (2.5% of 679 patients), nausea (1.6%), and dysmenorrhea (1.5%). It is contraindicated in patients hyper-sensitive to any of its ingredients.

• CAMPTOSAR. A chemotherapeutic agent for colorectal cancer, irinotecan HCt injection (Camptosar, Pharmacia & Upjohn), has been given FDA approval. It is indicated for the treatment of patients who have metastatic carcinoma of the colon or rectum that has recurred or progressed after 5-FU-based therapy.

Approval was based on phase II open-label clinical studies involving 304 patients with metastasized colon or rectal cancer who had previously undergone 5-FU-based therapy. In patients receiving irinotecan (median of 3 to 3.5 courses of therapy at median dosages of 54 to 62 mg/m2/week, the response rate ranged from 7.8% to 20.8% in a dose-dependent manner. Two patients had a complete response and 27 patients had a partial response.

The recommended starting dose for this drag is 125 mg/m2, and all doses should ,be administered as an IV infusion over 90 minutes. A course of therapy includes a weekly dose for 4 weeks, followed by a 2-week rest period. Additional courses may be administered every 6 weeks (4 weeks on irinotecan therapy then 2 weeks off). Subsequent dosages should be adjusted up to a maximum of 150 mg/m2 or as low as 50 mg/m2, depending on the patient’s tolerance.

Adverse events reported most often during clinical trials of irinotecan were grades 1 to 4 diarrhea (87.8%), nausea (86.2%), asthenia (75.7%), and vomiting (66.8%). The alopecia rate was 60.5%. Neutropenia, at times severe, was reported in 53.9% of patients. Diarrhea and nausea were the dose-limiting toxicities in phase I trials.

Irinotecan is contraindicated in patients with known hypersensitivity to it.

The average wholesale price of irinotecan is $395 per single-treatment vial.

• CEREBYX. An anticonvulsant drug — fosphenytoin sodium injection (Cerebyx, Parke-Davis) — has received FDA approval for short-term use when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous.

This drug will replace injectable phenytoin (Dilantin) by January 1, 1997, while oral phenytoin will remain on the market. Fosphenytoin overcomes some of injectable phenytoin’s limitations, providing a faster rate of IV administration (a mean of 5 to 7 minutes compared with 15 to 20 minutes for phenytoin) and reduced incidence of pain and burning at the infusion site.

Labeling states that the drug’s safety and effectiveness have not been evaluated for use beyond 5 days. Fosphenytoin can be used for the control of generalized convulsive status epilepticus and for prevention and treatment of seizures during neurosurgery. It also can provide a short-term substitute for oral phenytoin.

During clinical trials, only 9% of patients treated with IV fosphenytoin (n = 90) developed local intolerance versus 90% of patients treated with IV phenytoin (n = 22). Infusion was disrupted in 21% of patients in the first group compared with 67% in the second, and average infusion times were 13 and 44 minutes, respectively. According to labeling, IM administration, useful in short-term, nonemergency clinical situations, was also well tolerated.

The dose, concentration in dosing solutions, and infusion rate of fosphenytoin are expressed as phenytoin sodium equivalents (PE); therefore, no adjustments in the recommended dosage should be made when substituting this product for phenytoin sodium or vice versa, labeling warns.

For status epilepticus therapy, the recommended loading dose of fosphenytoin is 15 to 20 mg PE/kg, administered IV at a rate of 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should not be administered faster than 150 mg PE/min.

Continuous electrocardiogram, blood pressure, and respiratory function monitoring should be performed during the time when maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of infusions. The loading dose should be followed by maintenance doses of this drug (4 to 6 mg PE/kg/day) or phenytoin, given either orally or parenterally. Intramuscular administration should not be used in status epilepticus.

The recommended dosage for use in nonemergent seizures is 10 to 20 mg PE/kg, IM or IV, as a loading dose. Again, the rate of IV infusion should not exceed 150 mg PE/min, and the same monitoring should be performed as in status epilepticus. When substituting fosphenytoin, either IV or IM, for oral phenytoin, the same total daily dose is used.

Fosphenytoin for IV infusion should be diluted with 5% dextrose or 0.9% saline solution to a concentration ranging from 1.5 to 25 mg PE/ml.

The most commonly reported adverse drug reactions during clinical trials in which fosphenytoin was administered IV to patients with epilepsy or during neurosurgery were pruritus (48.9% of 90 patients), nystagmus (44.4%), dizziness (31.1%), and somnolence (20.0%). The drug is contraindicated in patients hypersensitive to it, any of its ingredients, phenytoin, or any other hydantoins.

The average wholesale price of fosphenytoin is $45 per 10 mL vial, which contains half the emergency dose.
NEW INDICATIONS

• BIAXIN. Clarithromycin tablets and granules for oral suspension (Biaxin, Abbott Laboratories) have been approved for a new indication in children — the treatment of community-acquired pneumonia caused by Mycoplasma pneumoniae, Chlamydia pneumoniae, or Streptococcus pneumoniae. It is already approved for this indication in adults. Clarithromycin also is approved for a variety of infectious diseases in children.

Approval was based on clinical studies involving children 3 to 12 years of age, primarily with pneumonia caused by Mycoplasma and Chlamydia microorganisms, which compared the drug with erythromycin. Of patients treated with oral clarithromycin 98% (121 of 175 patients) were cured or improved, compared with 95% (105 of 110) of those treated with erythromycin. Four to 6 weeks after treatment, one erythromycin-treated patient had pneumonia recurrence, compared with none in the clarithromycin group.

The recommended dosage for the new indication is 15 mg/kg/ day divided q12h for 10 days.

• PRAVACHOL. Pravastatin sodium tablets (Pravachol, Bristol-Myers Squibb) have been approved by the FDA for an additional indication, the primary prevention of coronary events in hypercholesterolemic patients without clinically evident coronary heart disease; namely, to reduce the risk of myocardial infarction (MI), to reduce the risk of undergoing myocardial revascularization procedures, and to reduce the risk of cardiovascular mortality with no increase in death from noncardiovascular causes. The HMG-CoA reductase inhibitor is already approved for use in the treatment of atherosclerosis and hypercholesterolemia.

Pravastatin was found in the 7-year West of Scotland Coronary Prevention Study to reduce the rate of nonfatal M1 and death from congestive heart disease by 31% when compared with placebo in men (n = 6,595; aged 45 to 64 years) with hypercholesterolemia (LDL cholesterol 156 to 254 mg/dl) but no history of MI (P = 0.0001). It also significantly reduced the risk for undergoing myocardial revascularization procedures (ie, coronary artery bypass graft surgery or coronary angioplasty) by 37% (P = 0.009). The rate of cardiovascular deaths dropped 32% (P = 0.03) in patients receiving pravastatin.

The dosage recommended for this indication is the same as for previously approved indications: 10 or 20 mg once daily at bedtime. In patients with primary hypercholesterolemia and a history of significant renal or hepatic disease or in elderly patients, a starting dose of 10 mg daily at bedtime is recommended. Administration of this drug should be accompanied by a cholesterol-lowering diet.

• ZITHROMAX (Zithromax online). The broad-spectrum antibiotic azithromycin (Zithromax, Pfizer Labs), has been approved by the FDA for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. The recommended dose is 1,200 mg taken once weekly, with or without rifabutin.

The agent also was approved in a new doseform for the indication: 600 mg tablets. It had been available only in capsules and suspension in 100 to 250 mg doses to treat a variety of mild-to-moderate infections in both adults and children.

Two randomized, double-blind clinical trials in patients with CD4 counts below 100 cells/mul have shown that prophylaxis with the drug, given at the recommended dose of 1,200 mg (two 600 mg tablets) once weekly, significantly reduces the risk of developing MAC bacteria in the bloodstream.

In a placebo-controlled trial, compared with placebo (n = 89), patients receiving azithromycin (n = 85) had significantly lower 1 year cumulative incidence rates of disseminated MAC disease (8.2% versus 19.1%, a drop of 10.9%; P < 0.05).

In trials with rifabutin, patients on azithromycin monotherapy (n = 223) had 1 year cumulative incidence rates of 7.6% versus 15.2% for patients taking rifabutin (P < 0.05). Both therapies were higher than the 2.8% incidence rate seen with azithromycin and rifabutin combination therapy (P < 0.001).

In the two trials, most adverse events associated with azithromycin therapy were related to the gastrointestinal tract: diarrhea (52% for the placebo-controlled trial and 50.2% for the comparative trial), nausea (32.6% and 27.0%, respectively), and abdominal pain (27% and 32.2%).
NEW FORMULATIONS

* CYTOGAM. A new formulation of cytomegalovirus immune globulin intravenous, human — a solution for injection — is now available (CytoGam, Massachusetts Public Biologic Labs). The solution contains 50 +/- 10 mg/ml, with 50 mg sucrose and 10 mg albumin (human)/ml. The solvent deter-gent-treated product, which is approved for the attenuation of primary cytomegalovirus disease associated with kidney transplantation, comes in 50-ml vials. The dose and administration schedule is the same as the previous formulation.
* DOVONEX. A new formulation of calcipotriene (Dovonex, Bristol-Myers Squibb) has gained FDA approval. A 0.005% cream now joins the 0.005% ointment for the treatment of plaque psoriasis.
* FRAGMIN. A new, once daily dosage strength of dalteparin sodium (Fragmin, Pharmacia & Upjohn) has received FDA approval. The low molecular weight heparin is now available in a 5,000 IU dosage for prophylaxis against deep vein thrombosis (DVT) in patients undergoing abdominal surgery. Previously, only a 2,500 IU once-daily dosage was available. According to the manufacturer, the two dosage strengths of dalteparin sodium allow prophylaxis of DVT to be tailored to each patient’s degree of risk.
* KADIAN. An oral, sustained-re-lease formulation of morphine in capsules (Kadian, manufactured by Purepac Pharmaceutical, marketed by Zeneca Pharmaceuticals) has been approved for once or twice daily dosing when moderate to severe pain management with an opioid analgesic is indicated for more than a few days.

In two controlled clinical trials, patients with moderate to severe cancer pain were randomly assigned to receive 7 days of either the sustained release morphine capsules once daily or 12-hour controlled-release morphine. All patients had received immediate-release morphine for at least 3 consecutive days before starting the trial.

Patients receiving the once-daily sustained release formulation had similar results as the 12-hour dosage formulation in terms of pain relief, use of rescue medication, global assessment by patient and investigator, and quality of sleep.

The capsule formulation can be administered on either a once-a-day or twice-a-day schedule, labeling states. Patients who have not developed a tolerance to opioids should be started on the 20 mg strength, which can be increased at a rate not greater than 20 mg every other day. Because most patients will develop tolerance, dosage adjustments will be needed to individualize the dosage. Labeling also provides recommendations for converting patients to and from the sustained-release formulation.

Labeling warns patients to swallow the capsules whole because taking broken, chewed, or crushed capsules could lead to a potentially toxic dose of morphine.

• RISPERDAL. A 1 mg/ml oral solution formulation of the antipsychotic drug risperidone (Risperdal, Janssen Pharmaceutica) has gained FDA approval. The medication, which is indicated for management of the manifestations of psychotic disorders, had been available only in a tablet formulation.

The recommended dose for the solution formulation is the same as for the tablet formulation: 1 mg twice daily to start, titrated up to 3 mg twice daily by the third day of treatment.
MISCELLANEOUS NOTES

* DERMATOP. The medium potency corticosteroid prednicarbate cream 0.1% (Dermatop, Hoechst Marion Roussel) has gained supplemental approval for use in pediatric patients.
* DOXIL. Labeling that extends the shelf-life of the liposomal agent doxorubicin (Doxil, Sequus) has been approved by the FDA. The shelf-life of the drug, approved for the second-line treatment of Kaposi’s sarcoma in patients with AIDS, has been increased from 14 to 20 months.
* FENTANYL ORALET. The narcotic analgesic fentanyl transmucosal system (Fentanyl Oralet, Abbott) has received supplemental approval for use in children who weigh between 10 and 15 kg. The labeling had previously recommended use of the drug in only children and adults who weighed at least 15 kg. The product is recommended as an anesthetic pre-medication and to induce conscious sedation.
* HALClON, XANAX. A “Dear Doctor” letter has been issued for triazolam tablets (Halcion, Pharmacia & Upjohn) and alprazolam tablets (Xanax, Pharmacia & Upjohn) warning of potential interactions with foods and other drugs. The letter states that the two drugs are metabolized via the cytochrome P450 3A pathway and may ketoconazole, itraconazole, and other medications and substances that significantly inhibit oxidative metabolism mediated by the cytochrome pathway.
* LORTAB 10/500 CIII. The analgesic combination of hydrocodone bitartrate [10 rag] and acetaminophen [500 rag] (Lortab 10/500 CIII, UCB Pharma) in a tablet is now available. According to the manufacturer, the combination tablet offers the lowest acetaminophen content of any 10 mg hydrocodone-containing product.

The suggested dose to relieve pain is one tablet every 4 to 6 hours, not to exceed an acetaminophen dose of 4,000 mg/day.

• MYOTROPHIN. An early access application has been granted by the FDA for insulin growth factor-1 (Myotrophin, codeveloped by Chiron and Cephalon) for preapproval distribution to patients suffering from amyotrophic lateral sclerosis (ALS; Lou Gehrigs disease).

The dosage to be used in the early access program will be 0.1 mg/kg/day given by subcutaneous injection. If able, patients will self-administer the drug.

Patients being considered for inclusion in this early access program must have a confirmed diagnosis of ALS, but a representative of Cephalon says that the supply is not yet adequate to meet the expected demand. Physicians wishing to register patients for potential selection to this program may call the Myotrophin Expanded Access Center at 800-829-3054.

* NORVASC. The calcium channel blocker amlodipine besylate (Norvasc, Pfizer) has revised labeling showing it to be safe for use in treating patients with hypertension or patients with angina who also have congestive heart failure. The FDA approved the revisions based on data from the Prospective Amlodipine Survival Evaluation (PRAISE) trial last year.
* OXYCONTIN. The manufacturer of oxycodone HCL controlled-re-lease (OxyContin, Purdue Pharma LP) and morphine sulfate con-trolled-release (MS Contin, Purdue Pharma LP) has issued a “Dear Health Care Professional” letter warning that some of its conversion calculators or slide cards are incorrect, and that all such conversion calculators for both products should be immediately discarded.

The conversion calculators show the recommended dose when converting from other oral, parenteral, and transdermal opioids to the oxycodone or morphine sulfate controlled-release products. Some cards were not cut correctly, the letter states, which could cause a misalignment of the recommended conversion dose leading the practitioner to read the dosage one level higher or lower than intended. A misaligned reading could cause the recommended conversion dose to be potentially toxic in a small number of patients.

• PROTEASE INHIBITORS. The FDA has issued a “Dear Health Care Professional” letter warning of spontaneous bleeding episodes in HIV-positive patients with hemophilia who were being treated with protease inhibitors at the time of the event.

The FDA and the drug manufacturers recommend that health care providers monitor hemophiliac patients for spontaneous bleeding episodes whenever any of the pro-tease inhibitors is used as part of an HIV treatment. However, because there is no conclusive evidence that the protease. inhibitors were the cause of the bleeding episodes, “health care providers and patients should not hesitate to initiate therapy with these drugs.”

Of the 15 cases of spontaneous bleeding preliminarily associated with these drugs, 11 involved hematomas and 5 hemarthroses (one patient reporting both). None involved serious injury or death, and most patients continued their protease inhibitor therapy. To date, all cases reported have involved European patients. There have been no reported cases in the United States.

• REDUX. The antiobesity product dexfenfluramine (Redux, Wyeth-Ayerst) has issued a “Dear Health Care Professional” letter warning of the risk of primary pulmonary hypertension.

The letter notes that the final data analysis from the International Primary Pulmonary Hypertension Study (IPPHS) found the risk of primary pulmonary hypertension (PPH) in patients taking an anorexigen for 3 or more months to be about 23 times higher than nonusers (between 23 and 46 cases per million patients per year). Labeling had reported the risk to be about 9 times higher (18 cases per million persons per year), based on a preliminary evaluation of the IPPHS data.

Because of the estimated 4-year 45% mortality rate associated with PPH, the letter warns that “it is very important” that dexfenfluramine not be prescribed for cosmetic weight loss. Rather. it should be kept to its approved indications Labeling is being revised to indicate the final data analysis.

* SELDANE. A “Dear Health Care Professional” letter has been issued for terrenadine (Seldane, Hoechst Marion Roussel) reminding of contraindications of terfenadine products in patients taking ketoconazole, itraconazole, erythromycin, clarithromycin, or troleandomycin, or in patients with significant hepatic dysfunction. The letter also points out that concomitant use of terrenadine with the macrolide antibiotics or azole antifungals, use in patients with significant hepatic dysfunction, or overdosage may result in serious cardiovascular events, including death, cardiac arrest, torsades de pointes and other ventricular arrhythmias. In addition, it stresses that the recommended daily dose of terrenadine should not be exceeded.
* VANTIN. A shortened dosing regime for treating tonsillitis and pharyngitis caused by Streptococcus pyogenes has been cleared by the FDA for cefpodoxime proxetil (Vantin Oral Suspension and Tablet, Pharmacia & Upjohn). The formulations can be prescribed to adults and children in twice-daily dosages of 5 mg/kg for the oral suspension or a 100 mg tablet for a 5 to 10 day regimen.

The former dosing regimen for treatment of pharyngitis and tonsillitis was 100 mg twice-a-day for adults (13 years and older) and 5 mg/kg twice-a-day for children (5 months to 12 years old) for 10 days.