Fulvestrant

IN THIS ARTICLE, you'll learn about eight more new drugs marketed in the first half of 2002. (For details on other new drugs first marketed in that period, see "New Drugs2003, Part I" in the February issue of Nursing2003.) Among the most significant are:

* pegfilgrastim, a longer-acting blood builder for chemotherapy patients

* ibritumomab tiuxetan, linked with yttrium-90 (Y-90) as the first radioimmunotherapy treatment approved for non-Hodgkin's lymphoma (NHL)

* etonogestrel and norelgestromin (each combined with ethinyl estradiol), two new twists on hormonal contraceptives.

Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult the package insert, a pharmacist, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs.

Anticoagulant

Fondaparinux sodium

An antithrombotic indicated after hip or knee surgery

Fondaparinux sodium (Arixtra; Organon, SanofiSynthelabo, Inc.) is the first antithrombotic agent approved for preventing deep vein thrombosis (DVT) in patients undergoing surgery to repair hip fractures. This drug also is indicated to prevent DVT in patients undergoing hip or knee replacement surgery, It's similar in action to the low-molecular-weight heparins (LMWHs). In comparison to heparin, fondaparinux has a long duration of action and requires less lab monitoring: Coagulation tests such as prothrombin time and activated partial thromboplastin time aren't sensitive measures of fondaparinux activity.

As with other anticoagulants, the potential for hemorrhage is the most significant safety concern. The effects of heparin and LMWH can be reversed with protamine, but no antidote exists for fondaparinux.

Compared with enoxaparin, which also is indicated for DVT prevention, fondaparinux was found to be more effective in clinical trials. The new drug is being studied for other uses, including prevention of ischemic complications in patients with unstable angina and non-Q-wave myocardial infarction.

Precautions: (1) Contraindicated in patients with active major bleeding or bacterial endocarditis and in patients with thrombocytopenia associated with a positive test for antiplatelet antibodies in the presence of fondaparinux. (2) Also contraindicated in patients with severe renal impairment and in those who weigh less than 110 pounds (50 kg), who are at greater risk for bleeding; because the uncalibrated syringes are prefilled, health care providers can't administer a reduced dose. (3) Use with extreme caution in patients with an increased risk of hemorrhage (including those with uncontrolled hypertension or a history of recent ulcerative gastrointestinal disease). (4) Use with caution in patients who are being treated with antiplatelet medications such as aspirin. (5) Use with caution in patients receiving epidural or spinal anesthesia or undergoing spinal puncture because of the risk of spinal or epidural hematomas.

Adverse reactions: anemia, fever, nausea, vomiting, constipation, edema, rash, insomnia, bleeding, hematomas related to spinal or epidural anesthesia or spinal puncture, thrombocytopenia, elevation of serum aminotransferases

Supplied as: 2.5 mg in 0.5-ml single-dose prefilled syringes with a 27-gauge, 1/2-inch needle and an automatic needle protection system

Dosage: 2.5 mg once daily as a subcutaneous (S.C.) injection. The initial dose should be given 6 to 8 hours after surgery, once hemostasis is established.

Nursing considerations:

(1) Monitor the patients renal function periodically and discontinue fondaparinux if he develops severe renal impairment (creatinine clearance of less than 30 ml/minute) or labile renal function.

(2) Administer the S.C. injection in fatty tissue in the abdomen and alternate injection sites. (3) Monitor for signs of bleeding, such as black, tarry stools; pink-- tinged urine; and easy bruising. (4) Teach the patient ways to decrease bleeding risk, such as using a soft toothbrush to help prevent gum bleeding.

Pegfilgrastim

Longer-lasting blood-cell builder

Produced by recombinant DNA technology, pegfilgrastim (Neulasta, Amgen) is a human granulocyte colony-- stimulating factor designed to increase neutrophil production. Pegfilgrastim can help reduce the incidence of infection (as manifested by febrile neutropenia) in patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy.

Although pegfilgrastim has the same pharmacologic actions as filgrastim, it has a much longer duration of action. As a result, it's given in just one S.C. dose per chemotherapy cycle; filgrastim must be given daily for up to 14 days.

Like tilgrastim, pegtilgrastim acts on a cell receptor that is found in some tumor types, such as myeloid tumors. Consequently it could act as a growth factor for these tumors. Pegfilgrastim hasn't been studied in patients with myeloid tumors.

Precautions: (1) Contraindicated in patients with known hypersensitivity to filgrastim or to Escherichia coli-derived proteins. (2) Use with caution in patients at serious risk for complications reported with filgrastim.

Adverse reactions: medullary bone pain, leukocytosis

Supplied as: 6 mg of pegfilgrastim in 0.6 ml in a single-- dose syringe with a 27-gauge, 1-inch needle

Dosage: 6 mg S.C. injection once per chemotherapy cycle. See the product information for more details on administration.

Nursing considerations:

(1) Because pegfilgrastim is supplied in a fixed dose formulation, don't administer it to children or adolescents weighing less than 99 pounds (45 kg). (2) Monitor neutrophil counts more frequently in patients taking lithium concurrently because lithium may increase the release of neutrophils. (3) Evaluate patients complaining of left upper quadrant or shoulder pain for enlarged or ruptured spleen. (4) Evaluate neutropenic patients for possible acute respiratory distress syndrome if they develop fever, lung infiltrates, or respiratory distress. (5) Keep patients with sickle-cell disease who are receiving pegfilgrastim well hydrated and monitor for sickle-cell crisis. (6) Store pegfilgrastim in the refrigerator and keep the syringes in their cartons to protect the drug from light.

Fulvestrant

Targeting metastatic breastcancer in older women

Many breast cancers have entrogen receptors; because estrogen can stimulate tumor growth, treatment usually includes an antiestrogen drug such ad tamoxifen. Fulvernt (Faslodex, AstraZeneca) is an estrogen receptor antagonist similar to tamoxifen, binding to estrogen receptors and causing down-regulation or degradation of the estrogen reception or protein in breast cancer cells. Administered via intramuscular (I.M.) injection, the drug is indicated for hormnone-receptor positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. Although breast cancer cell lines that are usually also resistant to fulvestrant, the new drug does inhibit growth of tamoxifenresistant cancers in some patients.

Fulvestrant generally shouldn't be used in patients taking anticoagulants or ir those with bleeding disorders or thrombocytopenia. Adverse reactions include nausea, vomiting, constipation or diarrhea, pain (including abdominal pain, bone pain, back pain, and headache), asthenia, hot flushes, phaiyngitis, dyspnea, and injection-site reactions.

The drug is supplied as prefilled syringes at a concentration of 50 mg/ml. The dose is 250 mg, which may be given as one injection (using a 5-ml refilled syringe) or two injections (using two prefilled 2.5-ml syringes). Give each dose via slow LM. injection into the buttock once a month. See the product labeling for complete dosage and administration guidelines.

Most patients prefer taking an oral antiestrogen drug such as tamoxifen to undergoing LM. injections. However, the once-a-month LM. route may be a plus for a patient who can't maintain a daily oral regimen.

Triptorelin pamoate

Palliative treatment for prostate cancer

Triptorelin pamoate (Trelstar Depot and Trelstar LA, Pharmacia), a luteinizing hormone-releasing hormone (LHRH) agonist, is indicated for palliative treatment of prostate cancer. Like the two other LHRH agonists, leuprolide and goserelin, it inhibits cancer growth by reducing serum testosterone levels to concentrations equivalent with castration.

It's an alternative to orchiectomy or estrogen administration when these treatments aren't indicated or are unacceptable to the patient. The drug is also being studied for use in treating endometriosis, uterine fibroids, and precocious puberty.

Triptorelin is contraindicated in patients hypersensitive to other LHRH agonists because it may cause angioedema and anaphylaxis.

Don't use triptorelin concurrently with medications that may cause hyperprolactinemia because this would reduce triptorelin's effectiveness.

The most common adverse reactions are hot flushes, skeletal pain, impotence, headache, and injection-site pain. Because triptorelin causes a transient increase in serum testosterone concentrations, patients may experience a worsening of prostate cancer symptoms or onset of new symptoms for the first several weeks of treatment. These symptoms include bone pain, neuropathy; hematuria, and bladder outlet or urethral obstruction.

Triptorelin is supplied as a lyonhilized powder in single-dose vials containing 3.75 mg (Trelstar Depot) and 11.25 mg (Trelstar LA) of triptorelin base. Both formulations are available in a single-dose delivery system that includes a syringe prefilled with diluent.

The recommended dosage of triptorelin is 3.75 mg once a month or 11.25 mg every 84 days, administered LM. into the buttock. Treatment usually is initiated with the once-a-month regimen and changed to the less-frequent regimen based on patient response. Rotate the injection site periodically. See the product labeling for complete dosage and administration guidelines.

Reconstitute the drug only with sterile water for injection. Shake the vial well; the resulting suspension should have a milky appearance. Administer it immediately after reconstitution.

Ibritumomab tiuxetan

Monoclonal antibody teams up with radiation to kill cancer cells Non-Hodgkin's lymphoma (NHL) is the sixth most common type of cancer in the United States (excluding nonmelanoma skin cancers). Standard therapy consists of radiation, chemotherapy, or both. Since 1997, immunotherapy with rituximab, a monoclonal antibody (MAB) that targets tumor cells, has also been an option.

Ibritumomab tiuxetan (Zevalin, Idec) is a new MAB that can be tagged with the radioactive agents indium- 111 (In-111) and yttrium-90 (Y-90). Ibritumomab is linked to In-ill for imaging purposes and to Y-90 for therapeutic effects; Y-90 can penetrate bulky or poorly vascularized tumors to kill cancer cells that the MAB alone can't reach.

Approved under the Food and Drug Administration's (FDA's) accelerated approval process, ibritumomab is indicated for patients with relapsed or refractory low-grade follicular or transformed B-cell NHL, including patients with follicular NHL refractory to rituximab.

Ibritumomab shouldn't be used in patients with 25% or greater lymphoma marrow involvement or impaired bone marrow reserve, or in patients with platelet counts less than 100,000 cells/mm^sup 3^.

Ibritumomab is contraindicated in patients with known hypersensitivity or anaphylactic reactions to murine proteins or any component of the treatment regimen. The drug's labeling includes a black-box warning because hypersensitivity and infusion reactions may be severe or fatal; treatment should be stopped in any patient who experiences a severe infusion reaction.

Other possible adverse reactions include thrombocytopenia, neutropenia, anemia, nausea, vomiting, abdominal pain, chills, fever, asthenia, dyspnea, pain, bacterial infection, hemorrhage secondary to thrombocytopenia, and myeloid malignancies and dysplasias (rare). Most adverse reactions are mild, but hematologic toxicity may be severe and prolonged.

Known as the Zevalin regimen, treatment with ibritumomab consists of two steps:

The patient first receives a rituximab infusion, followed within 4 hours by an infusion of In-111-linked ibritumomab for baseline whole body scanning. (Rituximab is given to reduce the number of circulating B cells, which maximizes the drug regimen's therapeutic effects on tumors.) Biodistribution of In-111 helps clinicians anticipate the effectiveness of the therapeutic treatment.

Seven to 9 days later, the patient receives a rituximab infusion, followed within 4 hours by an infusion of Y-90-linked ibritumomab to attack tumors.

The drug regimen is supplied in two kits, each with a vial containing 3.2 mg of ibritumomab in 2 ml of 0.9% sodium chloride injection. The radioactive agents and rituximab are obtained separately. Consult the product labeling for more details on dosage and administration.

Closely monitor the patient during treatment to prevent intravenous (LV) extravasation. After treatment, monitor his complete blood cell counts and platelet counts at least weekly until counts recover. Monitor him more frequently for thrombocytopenia if he's taking medications that interfere with platelet function or coagulation.

Treprostinil sodium

Easing the pressure of pulmonary arterial hypertension Rare and incurable, pulmonary arterial hypertension (PAH) is often not detected until its later and more severe stages. Constriction of smooth muscle cells in pulmonary blood vessels restricts blood flow to the lungs, causing damage that progresses to heart failure. The disorder can be either primary or secondary to many conditions, including scleroderma, connective tissue disorders, human immunodeficiency virus (HIV) infection, and overuse of appetite suppressants. Without treatment, patients can die within 2 years from onset of symptoms.

Treatments for PAH include anticoagulants, diuretics, calcium channel blockers, and epoprostenol, a prostaglandin that's a pulmonary and systemic vasodilator. In 2001, bosentan (Tracleer), the first of a new class of endothelin receptor antagonists, was approved for treating PAH. Although effective following oral administration, this drug is potentially teratogenic and hepatotoxic. (See "New Drugs2002, Part III," Nursing2002, July.)

Treprostinil (Remodulin, United Therapeutics) is an orphan drug that can be given as a continuous S.C. infusion for patients with PAH and heart failure whose symptoms are categorized in New York Heart Association (NYHA) Classes II through IV However, it probably will be reserved for use in patients with more severe symptoms (NYHA Classes III and IV) because of the complexity of administration and frequency of adverse reactions.

Treprostinil was approved under the FDAs accelerated approval process; studies evaluating the drug's efficacy are continuing. Similar in action to epoprostenol, it dilates pulmonary and systemic arterial vascular beds, helping to reduce dyspnea and fatigue associated with exercise. Although it hasn't been directly compared with epoprostenol, treprostinil may be less effective. However, treprostinil is given S.C. rather than via continuous IN infusion through a permanent indwelling central venous catheter, giving it a potential advantage over epoprostenol for some patients.

Treprostinil may excessively reduce blood pressure (BP) in patients taking medications to lower BP (such as antihypertensives or vasodilators). The drug also inhibits platelet aggregation, increasing bleeding risk, so use it with caution in patients on anticoagulation therapy Reduce the dosage in patients with hepatic insufficiency.

Possible adverse reactions include infusion-site pain, infusion-site reactions, headache, erythema, rash, diarrhea, nausea, jaw pain, vasodilation, and edema. Infusion-site reactions may be very painful; about 30% of patients in studies required opioids for pain relief.

Treprostinil is supplied as 20-ml vials at concentrations of 1 mg/ml, 2.5 mg/ml, 5 mg/ml, and 10 mg/ml. The drug is administered undiluted by continuous S.C. infusion via patient-inserted S.C. catheter and infusion pump. The initial dosage is 1.25 ng/kg/minute. Consult the product labeling for more information on titrating the dose upward to improve symptoms while minimizing adverse reactions.

A single reservoir (syringe) of treprostinil can be administered for up to 72 hours. A vial should be used for no more than 14 days after initial use.

Teach the patient how to self-administer the drug, making sure he knows how to insert and use the infusion equipment. Warn him against abruptly stopping therapy or suddenly reducing the dosage by a large amount, which could worsen his symptoms. To avoid possible interruptions of the infusion, tell him to have a backup infusion pump and S.C. infusion sets on hand at all times.

Monitor the patient for pain and provide analgesia as indicated. Assess for bleeding if he's on concurrent anticoagulation therapy and for hypotension if he's taking a diuretic, antihypertensive drug, or vasodilator.

Treprostinil is distributed by Priority Healthcare Corp. and Gentiva Health Services. The estimated cost of therapy for a year is over $50,000. However, for patients who can't pay, the drug is available free of charge through a compassionate use program.

THE TWO NEW HORMONAL contraceptive products marketed in 2002 feature not only new progestins, but also new routes of delivery-a vaginal ring and a transdermal patch.

Unlike oral contraceptives, these new products don't require daily dosing, a plus for women who sometimes forget to take a daily oral contraceptive. Such lapses are responsible for an estimated 300,000 unintended pregnancies a year in the United States. Also, although most women tolerate oral contraceptives well, the consistent release and concentrations of hormones from the ring and patch may be tolerated better by some women than the daily fluctuations of hormone levels associated with oral contraceptives.

Improved bioavailability makes these contraceptives effective at a lower hormone dose. Like other hormonal contraceptives, these products don't protect against sexually transmitted diseases, including HIV infection.

Serious adverse reactions to hormonal contraceptives include myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, hypertension, and decreased glucose tolerance. These risks are higher in women with such underlying problems as hyperlipidemia, obesity, and diabetes. Other possible adverse reactions include bleeding irregularities, gastrointestinal effects, fluid retention, headache, vaginal candidiasis, melasma, and rash.

Teach a patient using any hormonal contraceptive to immediately report to her health care provider any possible signs and symptoms of thromboembolism, such as chest pain, calf pain, or shortness of breath. Also inform her that many prescription and nonprescription medications and products, such as some antibiotics and St. John's wort, can diminish the contraceptive's effectiveness. Advise her to check with her provider before taking additional medications.

Etonogestrel/ ethinyl estradiol

This contraceptive ring protects for 3 weeks.

Etonogestrel/ethinyl estradiol (NuvaRing, Organon), a flexible ring inserted into the vagina, releases contraceptive hormones over a 3week period.

The NuvaRing shouldn't be used in women over age 35 who smoke 15 or more cigarettes per day. The ring also may be unsuitable for women with conditions that make the vagina more susceptible to irritation or ulceration.

Adverse reactions specific to the ring include spontaneous expulsion, foreign body sensations, vaginitis, headache, upper respiratory tract infection, leukorrhea, sinusitis, weight gain, and nausea.

The nonbiodegradable, flexible, transparent ring, which is slightly smaller than a diaphragm, contains 11.7 mg of etonogestrel and 2.7 mg of ethinyl estradiol. It releases 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily.

The ring should remain in place for 3 weeks, then be removed. Teach the patient to place the used ring in its reclosable foil pouch and discard it in a waste receptacle out of the reach of children and pets. She shouldn't flush it down the toilet.

During the week following ring removal, she should expect to experience withdrawal (menstrual) bleeding. She can insert a new ring 1 week after removing the last one, even if bleeding hasn't stopped.

If the ring is accidentally expelled, tell the patient she can rinse it with cool to lukewarm water and reinsert it within 3 hours. If more than 3 hours have passed, she can still reinsert the ring, but she should use backup contraception (such as condoms) for the next 7 days. Because the ring may interfere with correct placement of a diaphragm, she shouldn't rely on a diaphragm.

Norelgestromin/ ethinyl estradiol

Transdermal contraception with a weekly patch

Norelgestromin/ethinyl estradiol (Ortho Evra, Ortho-McNeil) provides hormonal contraception for 1 week via a transdermal patch. Although generally as effective as oral contraceptives, the patch may be less effective in women weighing more than 198 pounds (90 kg).

Adverse reactions specific to the patch include breast symptoms, headache, application-site reaction, nausea, upper respiratory infection, menstrual cramps, and abdominal pain.

The 20-cm^sup 2^ patch, which contains 6 mg of norelgestromin and 0.75 mg of ethinyl estradiol, releases 150 mcg and 20 mcg of the hormones, respectively, daily.

The transdermal system involves a 4-week cycle: The woman applies a new patch once a week for 3 weeks, followed by a patch-free week during which withdrawal bleeding usually occurs. She applies a new patch at the start of the next 4-week cycle. Teach her to fold a used patch in half so it sticks to itself and discard it out of the reach of children and pets.

Teach the patient to apply the patch to clean, dry, intact skin on the buttock, abdomen, upper outer arm, or upper torso (but not on the breasts). Tell her to avoid sites that are red, irritated, or injured and sites that might be rubbed by tight clothing. Also advise her to avoid using makeup, lotions, powders, or other topical products on the skin where the patch will be placed. Drug absorption isn't significantly affected by conditions such as a sauna, whirlpool, or cold water bath or pool.

The patch normally adheres well to the skin. If it detaches, she can reapply it, unless it's no longer sticky it's become stuck to itself or another surface, another material is stuck to it, or it's come off before. In those cases, she should immediately apply a new patch. She shouldn't use supplemental adhesives to hold the patch in place.

If the patch has been off more than 24 hours (or she's not sure how long it's been off), the effectiveness of contraception is uncertain. Rather than reapplying the patch, she should apply a new one. This starts a new contraceptive cycle, and she should use backup nonhormonal contraception for the first week she wears the new patch.

Each patch is packaged in a protective pouch and supplied in cartons containing three patches (for one cycle) or a single patch to use if a patch must be replaced.

SELECTED REFERENCES

Drug Facts and Comparisons. St. Louis, Mo., Facts and Comparisons, Inc., 2003. Nursing2003 Drug Handbook. Springhouse, Pa., Springhouse Corp., 2003. Physicians' Desk Reference, 57th edition. Montvale, NJ., Medical Economics, 2003.

BY DANIEL A. HUSSAR, PHD Remington Professor of Pharmacy Philadelphia College of Pharmacy University of the Sciences in Philadelphia, Pa.

Copyright Springhouse Corporation Jul 2003
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