FRAGMIN^® Indications

• Prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE)
  • In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness
  • In patients undergoing hip replacement surgery
  • In patients undergoing abdominal surgery who are at risk for thromboembolic complications
• Prophylaxis of ischemic complications in unstable angina (UA)* and non–Q-wave myocardial infarction (NQWMI), when concurrently administered with aspirin therapy
• Extended treatment of symptomatic venous thromboembolism (VTE; proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer

* With EKG changes

FRAGMIN^® Important Safety Information Prescribing Information

• FRAGMIN^® is contraindicated in patients with active major bleeding or with known hypersensitivity to the drug, heparin, or pork products, or with thrombocytopenia associated with a positive antiplatelet antibody test

• Patients undergoing regional anesthesia should not receive FRAGMIN^® for unstable angina or non–Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN^® for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN^® recommended for these indications

• FRAGMIN^® Injection is not intended for intramuscular administration

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

• 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 extreme caution in patients with history of heparin-induced thrombocytopenia

• In FRAGMIN^® clinical trials supporting non-cancer indications, platelet counts of <100,000/mm3 and <50,000/mm3 occurred in <1% and <1%, respectively

• In a clinical trial of patients with cancer and acute symptomatic VTE treated for up to 6 months in the FRAGMIN^® treatment arm, platelet counts of <100,000/mm3 occurred in 13.6% of patients, including the 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

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

• Each multiple-dose vial of FRAGMIN^® contains benzyl alcohol as a preservative [which] has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Because benzyl alcohol may cross the placenta, FRAGMIN^® preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed. If anticoagulation with FRAGMIN^® is needed during pregnancy, preservative-free formulations should be used, where possible

• FRAGMIN^® should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see PRECAUTIONS, Laboratory Tests). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non–Q-wave myocardial infarction (see DOSAGE AND ADMINISTRATION)

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

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

For more information about FRAGMIN^® please see full Prescribing Information.

HEXALEN^® Indications

HEXALEN^® (altretamine) capsules 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 agentbased
combination.

HEXALEN^® Important Safety Information Prescribing Information

CONTRAINDICATIONS

• HEXALEN^® capsules is contraindicated in patients who have shown hypersensitivity to it. HEXALEN^® capsules should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. HEXALEN^® capsules 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^® capsules has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. HEXALEN^® capsules may cause fetal damage when administered to a pregnant woman. If HEXALEN^® capsules 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^® capsules, and as clinically indicated (see Adverse Reactions).
• Drug Interactions
  • Concurrent administration of HEXALEN^® capsules 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^® capsules 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^® capsules and/or cisplatin (1).
• Carcinogenesis, Mutagenesis and Impairment of Fertility
  • The carcinogenic potential of HEXALEN^® capsules has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. HEXALEN^® capsules was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. HEXALEN^® capsules 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^® capsules 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^® capsules at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

Pregnancy

• Pregnancy Category D: see Warnings section.

Nursing Mothers

• 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^® capsules treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with HEXALEN^® capsules.

Pediatric Use

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

ADVERSE REACTIONS

• Gastrointestinal
  • With continuous high-dose daily HEXALEN^® capsules, 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^® capsules dose reduction or, rarely, discontinuation of HEXALEN^® capsules 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^® capsules. In 2 clinical studies of single-agent HEXALEN^® capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued HEXALEN^® capsules 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) capsules than moderate-dose HEXALEN^® capsules administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of HEXALEN^® capsules 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^® capsules and/or cisplatin (1).
• Hematologic
  • HEXALEN^® capsules 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.

ONTAK^® Indication

The treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor

ONTAK^® Important Safety Information Prescribing Information

Serious infusion reactions

• Infusion reactions are symptoms that occur within 24 hours of receiving ONTAK^® and disappear within 48 hours of receiving the last infusion in that cycle of treatment. In medical studies, infusion reactions were reported in 70.5% (165/234) ONTAK^®-treated patients.
• Serious infusion reactions were reported in 8% of patients.
• Patients who completed at least 4 cycles of ONTAK^® in a large medical study, experienced less infusion reactions in the 3rd and 4th cycles when compared to the 1st and 2nd cycles.

Capillary leak syndrome

• Capillary leak syndrome is the occurrence of at least 2 of the following 3 symptoms (low blood pressure, edema, low blood albumin) at any time during ONTAK^® therapy. These symptoms do not have to occur at the same time.
• In medical studies, capillary leak syndrome was reported in 32.5% (76/234) of ONTAK^®-treated patients; one-third of those 76 patients required hospitalization or needed medical treatment to prevent hospitalization.
• The start of symptoms in patients with capillary leak syndrome may be delayed, and can occur up to 2 weeks after receiving an infusion. Symptoms may stay the same or get worse after stopping ONTAK^®.
• You will be regularly checked for weight gain, new or worsening edema and low blood pressure (including any dizziness when you stand up or sit up in bed).
• Your blood albumin levels will be monitored before you receive each course of ONTAK^® and more often if needed. You will not receive ONTAK^® if you have low blood albumin.

Visual loss

• Loss of visual acuity, usually with loss of color vision has been reported after receiving ONTAK^®.
• Recovery was reported in some of the affected patients, but most patients reported that their visual impairment stayed the same.

Most common side effects

• In medical studies, more than 20% of the 234 ONTAK^®-treated patients experienced fever, nausea, tiredness, chills, vomiting, diarrhea, headache, swelling of the ankles or fingers, cough, shortness of breath and itching.
• The most common serious side effects were capillary leak syndrome (11%), infusion reactions (8%), and visual changes including loss of visual acuity (4%).
• ONTAK^® was stopped in 28.2% of patients due to side effects.

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

Targretin ^® Capsules 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.