Activella^® ([estradiol/norethindrone acetate] tablets) Indications and Usage

Activella^® 0.5 mg/0.1 mg is indicated in women who have a uterus for the treatment of moderate to severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

Activella^® 1.0 mg/0.5 mg is also indicated in women who have a uterus for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When used solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

For additional information about Activella^® please refer to Prescribing Information, including boxed warning.

Activella^® Important Safety Information

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia in prescribing information.)

The estrogen plus progestin substudy of the Women’s Health Initiative (WHI) reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer in prescribing information.)

The estrogen-alone substudy of the WHI reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders in prescribing information.)

The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with CE 0.625 mg combined with MPA 2.5 mg and during 5.2 years of treatment with CE 0.625 mg alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use in prescribing information.)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these trials, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Other warnings include: gallbladder disease, hypercalcemia, and visual abnormalities.

Activella^® should not be used in women with any of the following conditions: undiagnosed abnormal genital bleeding; known, suspected, or history of cancer of the breast; known or suspected estrogen-dependent neoplasia; active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction); liver dysfunction or disease; known hypersensitivity to the ingredients of Activella^® 0.5 mg/0.1 mg or Activella^® 1.0 mg/0.5 mg; known or suspected pregnancy.

In a clinical trial, the most commonly reported adverse events (reported at a frequency of ≥5%) were back pain, headache, pain in extremity, nausea, diarrhea, nasopharyngitis, endometrial thickening, and vaginal hemorrhage.

Vagifem^® (estradiol vaginal tablets) Indications and Usage

Vagifem^® is indicated for the treatment of atrophic vaginitis.

Vagifem^® Important Safety Information

For additional information about Vagifem^® please refer to Prescribing Information, including boxed warning.

ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA.

Three independent, case-controlled studies have reported an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for more than one year. This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incident rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer-reporting systems, an increase of which may be related to the rapidly expanding use of estrogens during the last decade.

The three case-controlled studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration and treatment and on estrogen dose. In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed, on at least a semiannual basis, to determine the need for continued therapy.

Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or reoccurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy. There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equi-estrogenic doses.

Other warnings include: induction of malignant neoplasms, gallbladder disease, effects similar to those caused by estrogen-progestogen oral contraceptives (such as thromoboembolic disease, hepatic adenoma, elevated blood pressure, worsening of glucose tolerance), hypercalcemia, and rarely, trauma induced by the Vagifem^® applicator.

In a placebo-controlled clinical trial, the most commonly reported adverse events included: headache (9%), abdominal pain (7%), upper respiratory tract infection (5%), genital moniliasis (5%), and back pain (7%).

The use of Vagifem^® is contraindicated in women who exhibit one or more of the following: known or suspected breast carcinoma, known or suspected estrogen-dependent neoplasia (e.g., endometrial carcinoma), abnormal genital bleeding of unknown etiology, known or suspected pregnancy, porphyria, hypersensitivity to any Vagifem^® constituents, active thrombophlebitis or thromboembolic disorders, or a past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast malignancy).

Levemir^® (insulin detemir [rDNA origin] injection) Indications and Usage

Levemir^® is indicated for once- or twice-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

Levemir^® Important Safety Information

Levemir^® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

Hypoglycemia is the most common adverse effect of all insulin therapies, including Levemir^®. As with other insulins, the timing of hypoglycemic events may differ among various insulin preparations. Glucose monitoring is recommended for all patients with diabetes. Levemir^® is not to be used in insulin infusion pumps. Any change of insulin dose should be made cautiously and only under medical supervision. Concomitant oral antidiabetes treatment may require adjustment.

Inadequate dosing or discontinuation of treatment may lead to hyperglycemia and, in patients with type 1 diabetes, diabetic ketoacidosis. Levemir^® should not be diluted or mixed with any other insulin preparations. Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Dose and timing of administration may need to be adjusted to reduce the risk of hypoglycemia in patients being switched to Levemir^® from other intermediate or long-acting insulin preparations. The dose of Levemir^® may need to be adjusted in patients with renal or hepatic impairment.

Other adverse events commonly associated with insulin therapy may include injection site reactions (on average, 3% to 4% of patients in clinical trials) such as lipodystrophy, redness, pain, itching, hives, swelling, and inflammation. Less common, but more serious are severe cases of generalized allergy, including anaphylactic reaction, which may be life threatening.

*Whether these observed differences represent true differences in the effects of Levemir^® and NPH insulin is not known, since these trials were not blinded and the protocols (eg, diet and exercise instructions and monitoring) were not specifically directed at exploring hypotheses related to weight effects of the treatments compared. The clinical significance of the observed differences in weight has not been established.

Please see Prescribing Information Prescribing Information at NovoMedLink.com.

Norditropin^® (somatropin [rDNA origin] injection) Indications and Usage

Norditropin^® (somatropin [rDNA origin] injection) is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone, the treatment of children with short stature associated with Noonan syndrome and Turner syndrome, and for the replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: 1. Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or 2. Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Norditropin^® Important Safety Information

Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses or in patients with active proliferative or severe non-proliferative diabetic retinopathy. Norditropin should not be used in patients with known hypersensitivity to somatropin or any of its excipients.

Somatropin should not be used or should be discontinued with any evidence of active malignancy. Patients with preexisting malignancy should be monitored carefully for any progression or reoccurrence.

Somatropin should not be used to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure as increased mortality may occur.

Deaths have been reported in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment and are treated with somatropin. Unless patients with Prader-Willi syndrome also have a diagnosis of GHD, Norditropin is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Blood glucose levels should be monitored periodically as treatment with somatropin may decrease insulin sensitivity. Patients with preexisting diabetes or glucose intolerance should be monitored closely during somatropin therapy. Doses of insulin or oral agents may need to be adjusted for patients with diabetes on somatropin therapy.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after initiation of somatropin therapy and generally resolve after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be discontinued.

Pediatric patients may develop slipped capital femoral epiphyses more frequently if they have endocrine disorders or during rapid growth. Any child having onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. Progression of scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis.

In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Patients treated with somatropin should therefore have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or adjusted as needed.

Patients with Turner Syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

Although from a clinical study in Noonan syndrome there was no evidence of somatropin-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy (as judged by echocardiography), the safety of Norditropin in children with Noonan syndrome and significant cardiac disease is not known.

Somatropin inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD-1) in adipose/hepatic tissue, and may significantly impact the metabolism of cortisol and cortisone. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy especially with cortisone acetate and prednisone for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses.

Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine) or other hormone replacement therapy.

The safety and effectiveness of Norditropin in patients age 65 years and older has not been evaluated in clinical studies. Elderly patients may be more sensitive to the actions of somatropin and may be more prone to develop adverse reactions.

Common somatropin-related adverse reactions include injection site reactions/rashes, lipoatrophy and headaches, glucose intolerance, fluid retention and unmasking of latent central hypothyroidism.

Most serious adverse reactions reported for somatropin include intracranial hypertension, diabetic retinopathy, glucose intolerance, slipped capital femoral epiphysis, progression of preexisting scoliosis, sudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection, and intracranial tumors as a 2nd tumor in patients who had been treated for a 1st neoplasm.

Please see Prescribing Information

NovoLog^® (insulin aspart [rDNA origin] injection) Indications and Usage

NovoLog^® is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

NovoLog^® Important Safety Information

NovoLog^® is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog^® or one of its excipients.

NovoLog^® has a more rapid onset and shorter duration of action than regular human insulin. An injection of NovoLog^® should be immediately followed by a meal within 5 to 10 minutes. Because of the short duration of action of NovoLog^®, a longer-acting insulin also should be used in patients with type 1 diabetes and may be needed in patients with type 2 diabetes. When used in an external subcutaneous insulin infusion pump, NovoLog^® should not be mixed with any other insulin or diluent. Hypoglycemia is the most common adverse effect of all insulin therapies, including NovoLog^®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulins.

Any change of insulin dose should be made cautiously and only under medical supervision. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using external pump infusion therapy. As with all insulin preparations, the time course of action of NovoLog^® may vary in different individuals or at different times in the same individual and is dependent on many conditions, including injection site, local blood supply, temperature, and level of physical activity.

Severe, life-threatening generalized allergy, including anaphylactic reaction, may occur with any insulin product, including NovoLog^®. Adverse reactions observed with NovoLog^® include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus. Insulin, particularly when given intravenously or in settings of poor glycemic control, may cause hypokalemia. Like all insulins, NovoLog^® requirements may be reduced in patients with renal impairment or hepatic impairment.

Please see Prescribing Information Prescribing Information at NovoMedLink.com.

NovoLog^® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]) Indications and Usage

NovoLog^® Mix 70/30 is indicated for the treatment of patients with diabetes mellitus for the control of hyperglycemia.

NovoLog^® Mix 70/30 Important Safety Information

NovoLog^® Mix 70/30 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog^® Mix 70/30 or one of its excipients.

Because NovoLog^® Mix 70/30 has peak pharmacodynamic activity 1 hour after injection, it should be administered with meals. Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog^® Mix 70/30. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, species, or method of manufacture may result in the need for a change in dosage. Potential side effects associated with the use of all insulins include hypoglycemia, hypokalemia, lipodystrophy, and allergic reactions.

Because of differences in the action of NovoLog^® Mix 70/30 and other insulins, care should be taken in patients in whom these conditions may be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, are using potassium-lowering drugs, or are taking drugs sensitive to serum potassium level). Do not mix NovoLog^® Mix 70/30 with any other insulin product.

As with other insulin therapy, erythema, swelling, and pruritus at the injection site have been observed with NovoLog^® Mix 70/30. Less common but more serious are severe cases of generalized allergy, including anaphylactic reaction, which may be life threatening. NovoLog^® Mix 70/30 dose requirements may be reduced in the presence of renal impairment or impaired hepatic function. Changes in cross-reactive antibodies were more common after NovoLog^® Mix 70/30 than with human premixed 70/30, but the clinical significance of these antibodies has not been established. Frequency of adverse events comparable with that of human 70/30. Local injection site reactions comparable with those of human 70/30.

Please see Prescribing Information Prescribing Information at NovoMedLink.com.

NovoSeven^® RT Coagulation Factor VIIa (Recombinant) Room Temperature Stable Indications and Usage

NovoSeven^® RT is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; treatment of bleeding episodes in patients with congenital FVII deficiency and prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

NovoSeven^® RT Important Safety Information

• The most common adverse events of NovoSeven^® RT therapy are pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema, and rash. The most serious adverse events observed during NovoSeven^® RT therapy are thrombotic events.
• Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (aPCCs/PCCs) may have a potential risk of developing thrombotic events in association with NovoSeven^® RT treatment.
• Use with caution in patients with known hypersensitivity to NovoSeven^® RT, its components, or mouse, hamster, or bovine proteins.
• Serious adverse events that may have been related to the use of NovoSeven^® RT in acquired hemophilia included thrombotic serious adverse events and death.
• Serious adverse events that may have been related to the use of NovoSeven^® RT occurred in 14 of 298 patients with hemophilia A or B with inhibitors in the initial clinical program.
• Development of antibodies against FVII has been reported in FVII-deficient patients after treatment with NovoSeven^® RT. These patients had previously been treated with human plasma and/or plasma-derived FVII. Factor VII deficient patients should be monitored for prothrombin time (PT) and factor VII coagulant activity before and after administration of NovoSeven^® RT.
• Concomitant use of NovoSeven^® RT with other formulations of NovoSeven^® is not recommended due to potential dosing errors based on different concentrations.

Please see Prescribing Information.

NovoSeven^® Coagulation Factor VIIa (Recombinant) Indications and Usage

For the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; treatment of bleeding episodes in patients with congenital Factor VII deficiency and prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

(Acquired only) For the treatment of bleeding episodes in patients with acquired hemophilia. For the prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia.

NovoSeven^® Important Safety Information

• Most common adverse events: pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema, and rash.
• Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (aPCCs/PCCs) may have a potential risk of developing thrombotic events in association with NovoSeven treatment.
• Contraindicated in patients with known hypersensitivity to NovoSeven, its components, or mouse, hamster, or bovine proteins.
• Serious adverse events that may or may not have been related to the use of NovoSeven in acquired hemophilia (10 of 139 patients in the compassionate use program, HTRS registry, and the published literature) may include thrombotic serious adverse events and death.
• Serious adverse events that may or may not have been related to the use of NovoSeven occurred in 14 of 298 patients with hemophilia A or B with inhibitors in the initial clinical program.
• Development of antibodies against FVII has been reported in FVII deficient patients after treatment with NovoSeven. These patients had previously been treated with human plasma and/or plasma-derived FVII.

Please see Prescribing Information.