FRAGMIN^®(dalteparin sodium injection) Indications

FRAGMIN^® is a low molecular weight heparin (LMWH) indicated for:

• Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction

• Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness

• Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in patients with cancer. In these patients, the FRAGMIN^® therapy begins with the initial VTE treatment and continues for six months.

FRAGMIN^® Limitations of Use

• FRAGMIN^® is not indicated for the acute treatment of VTE.

FRAGMIN^® Important Safety Information Prescribing Information

• FRAGMIN^® is contraindicated in patients with active major bleeding, history of heparin induced thrombocytopenia, hypersensitivity to dalteparin sodium, heparin, or pork products.

• FRAGMIN^® is contraindicated in patients undergoing epidural/neuraxial anesthesia as a treatment for unstable angina and non-Q-wave MI and for prolonged VTE prophylaxis due to an increased risk of bleeding associated with the dosage of FRAGMIN^® recommended for these indications.

• FRAGMIN^®, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage; bleeding can occur at any site during therapy. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site.

• FRAGMIN^® should be used with caution in patients with bleeding diathesis, thrombocytopenia or platelet defects, severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.

• FRAGMIN^® should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.
  • In FRAGMIN^® clinical trials supporting non-cancer indications, platelet count of <50,000/mm3 occurred in <1% of patients.
  • In FRAGMIN^® clinical trials supporting the extended treatment of symptomatic VTE in patients with cancer, platelet counts of <100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN^® arm and 8.1% of patients in the oral anticoagulant arm. FRAGMIN^® dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.

• Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with administration of FRAGMIN^®. The incidence of this complication is unknown at present. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed.

• Each multiple-dose vial of FRAGMIN^® contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN^® preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN^® is needed during pregnancy, use preservative-free formulations, where possible.

• Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN^®.

• The most commonly reported side effect is hematoma at the injection site.

• Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred. A few cases of anaphylactoid reactions have been reported.

• Use FRAGMIN^® with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding.

• FRAGMIN^® cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.

• FRAGMIN^® Injection is not intended for intramuscular administration.

For more information about FRAGMIN, please see Full Product Information.

HEXALEN^®(altretamine) Indications

HEXALEN^® (altretamine) is indicated for use as a single agent in the palliative treatment of patients
with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based
combination.

HEXALEN^® Important Safety Information Prescribing Information

CONTRAINDICATIONS

• HEXALEN^® is contraindicated in patients who have shown hypersensitivity to it. HEXALEN^® should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. HEXALEN^® has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.

Pregnancy: Category D

• HEXALEN^® has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. HEXALEN^® may cause fetal damage when administered to a pregnant woman. If HEXALEN^® is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

• General
  • Neurologic examination should be performed regularly (see Adverse Reactions).
• Laboratory Tests
  • Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of
    HEXALEN^®, and as clinically indicated (see Adverse Reactions).
• Drug Interactions
  • Concurrent administration of HEXALEN^® and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension (see Warnings section). Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine’s half-life and toxicity in a rat model.
  • Data from a randomized trial of HEXALEN^® and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with HEXALEN^® and/or cisplatin (1).
• Carcinogenesis, Mutagenesis and Impairment of Fertility
  • The carcinogenic potential of HEXALEN^® has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. HEXALEN^® was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. HEXALEN^® administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m2/day and was embryocidal at 240 mg/m2/day. Administration of 120 mg/m2/day HEXALEN^® to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with HEXALEN^® at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

Pregnancy

• Pregnancy: Category D under CONTRAINDICATIONS.

Nursing Mothers

• It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to HEXALEN^® treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with HEXALEN^®.

Pediatric Use

• The safety and effectiveness of HEXALEN^® in children have not been established.

ADVERSE REACTIONS

• Gastrointestinal
  • With continuous high-dose daily HEXALEN^®, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires HEXALEN^® dose reduction or, rarely, discontinuation of HEXALEN^® therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of HEXALEN^®. In 2 clinical studies of single-agent HEXALEN^® utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN^® due to severe nausea and vomiting.
• Neurotoxicity
  • Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous high-dose daily HEXALEN^® (altretamine) than moderate-dose HEXALEN^® administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of HEXALEN^® and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with HEXALEN^® and/or cisplatin (1).
• Hematologic
  • HEXALEN^® causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm3 occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm3. Thrombocytopenia below 50,000 platelets/mm3 was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).

Please see the HEXALEN^® full prescribing information including Boxed WARNINGS and additional important safety information.

Targretin ^® Capsules (bexarotene) Indication

Targretin^® capsules are indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Targretin^® Capsules Important Safety Information Prescribing Information

Pregnancy Category X

Targretin^® capsules must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Targretin^® capsules, Tagretin must be stopped immediately and the woman given appropriate counseling.

Lipid abnormalities

Targretin^® capsules induce major lipid abnormalities in most patients which must be monitored and treated during long term therapy. Fasting blood lipid determinations should be performed before therapy is initiated and weekly until the lipid response to Targretin^® is established (usually within 2-4 weeks) and at 8 week intervals thereafter. If fasting triglycerides are elevated or become elevated during treatment, antilipemic therapy should be instituted, and if necessary, the dose of Targretin^® should be reduced or suspended.

Concomitant administration of Targretin^® capsules and gemfibrozil resulted in substantial increases in plasma bexarotene and is not recommended.

Pancreatitis

Acute pancreatitis has been reported. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) should generally not be treated with Targretin^® capsules.

Liver function test abnormalities

Elevations of liver function tests (LFTs) have been observed. Baseline LFTs should be obtained, and LFTs should be carefully monitored after 1, 2 and 4 weeks of treatment initiation, and if stable, every 8 weeks thereafter during treatment. Suspension or discontinuation of Targretin^® capsules should be considered if test results reach >3 times the upper limit of normal values for SGOT/AST, SGPT/ALT, or bilirubin. Targretin^® capsules should only be used with great caution in patients with hepatic insufficiency.

Thyroid axis alterations

Targretin^® capsules can induce clinical hypothyroidism, causing a reversible reduction in thyroid hormone levels. Treatment with thyroid hormone supplements should be considered in these patients.

Baseline thyroid function tests should be obtained and patients monitored during treatment with Targretin^® capsules.

Leukopenia

Reversible leukopenia has been reported with treatment at certain doses of Targretin^® capsules.

Hypersensitivity to retinoids

Targretin^® capsules should be used with caution in patients with a known hypersensitivity to retinoids.

Photosensitvity

Retinoids as a class have been associated with photosensitivity. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light while receiving Targretin^® capsules.

Most common adverse events

The most commonly reported adverse events in clinical trials include hyperlipemia, hypercholesterolemia, headache, asthenia, hypothyroidism, leukpenia, and diarrhea.

Please see the Targretin^® Capsules full prescribing information including Boxed WARNING and additional important safety information.