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18 Clinical Rounds Dermatology I NTERNAL M EDICINE N EWS • May 1, 2006 Patient-Initiated Therapy Speeds Herpes Healing

BY BETSY BATES this “window of opportunity ...you ought initiated therapy within an hour, and de- and tenderness was more rapid in patients Los Angeles Bureau to be able to treat the patient with high- veloped vesicles. taking the single-dose of famciclovir than dose famciclovir if it’s initiated early in the The time to healing of primary vesicu- in those taking a split dose, starting with S AN F RANCISCO — A single, patient- course of an outbreak,” he said. “That was lar lesions was 4.4 days in 152 patients ran- 750 mg at the first prodromic sign and 750 initiated dose of famciclovir cut short re- the idea behind this study.” domized to receive 1,500 mg of famciclovir mg later that day. current outbreaks of herpes labialis by 2 Patients recruited from sites in the Unit- in a single dose, 4 days in 157 patients who Adverse events included headache and days, Dr. Marcus Conant said at the annual ed States, Canada, and Australia had took 2 doses of 750 mg each on the first nausea, but were similar in the active treat- meeting of the American Academy of healthy immune function and a history of day, and 6.2 days in 168 patients on place- ment and placebo arms. Dermatology. prodromal symptoms and vesicle forma- bo. The time to healing of all vesicular le- The magnitude of benefit was signifi- Viral replication of herpes simplex virus tion associated with at least half of their sions was 4.5 days and 4.1 days in the sin- cantly greater than that seen in studies of type 1 lasts 8 hours. Famciclovir remains previous facial herpes outbreaks. Of the gle- and split-dose treatment groups and topical treatments, noted Dr. Spotswood in a cell for 10 hours, he explained. Given 1,376 subjects, 477 experienced symptoms, 6.6 days with placebo. Resolution of pain Spruance of the University of Utah in a poster further detailing the findings. Acy- clovir cream shortens outbreaks by 0.5-0.6 weeks. On rare occasions, injection site reactions may require indicated that detemir and human insulin had similar discontinuation of LEVEMIR. effects regarding embryotoxicity and teratogenicity. day; penciclovir cream by 0.7-1 day; and In some instances, these reactions may be related to factors Nursing mothers docosanol cream by 18 hours. other than insulin, such as irritants in a skin cleansing agent or It is unknown whether LEVEMIR is excreted in significant poor injection technique. amounts in human milk. For this reason, caution should Still unclear is how efficient patient-ini- Systemic : Generalized allergy to insulin, which is less be exercised when LEVEMIR is administered to a nursing tiated therapy was in aborting outbreaks common but potentially more serious, may cause rash (including mother. Patients with who are lactating may require pruritus) over the whole body, shortness of breath, wheezing, adjustments in insulin dose, meal plan, or both. altogether. There was no significant dif- reduction in blood pressure, rapid pulse, or sweating. Severe Pediatric use ference in the proportion of patients in the Rx ONLY cases of generalized allergy, including anaphylactic reaction, may In a controlled clinical study, HbA1c concentrations and rates of BRIEF SUMMARY. Please see package insert for full be life-threatening. were similar among patients treated with LEVEMIR and patients treated with NPH human insulin. prescribing information. Intercurrent Conditions INDICATIONS AND USAGE Insulin requirements may be altered during intercurrent Geriatric use The challenge for LEVEMIR is indicated for once- or twice-daily subcutaneous conditions such as illness, emotional disturbances, or other Of the total number of subjects in intermediate and long-term administration for the treatment of adult and pediatric patients stresses. clinical studies of LEVEMIR, 85 (type 1 studies) and 363 (type physicians is to 2 studies) were 65 years and older. No overall differences in with mellitus or adult patients with type 2 Information for Patients convince patients diabetes mellitus who require basal (long acting) insulin for the LEVEMIR must only be used if the solution appears clear and safety or effectiveness were observed between these subjects control of . colorless with no visible particles. Patients should be informed and younger subjects, and other reported clinical experience to keep famciclovir has not identified differences in responses between the CONTRAINDICATIONS about potential risks and advantages of LEVEMIR therapy, elderly and younger patients, but greater sensitivity of some with them so they LEVEMIR is contraindicated in patients hypersensitive to insulin including the possible side effects. Patients should be offered older individuals cannot be ruled out. In elderly patients with detemir or one of its excipients. continued education and advice on insulin therapies, injection can take it technique, life-style management, regular monitoring, diabetes, the initial dosing, dose increments, and maintenance WARNINGS periodic glycosylated hemoglobin testing, recognition and dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia is the most common adverse effect of immediately. management of hypo- and hyperglycemia, adherence to meal Hypoglycemia may be difficult to recognize in the elderly. insulin therapy, including LEVEMIR. As with all , planning, complications of insulin therapy, timing of dosage, ADVERSE REACTIONS the timing of hypoglycemia may differ among various instruction for use of injection devices and proper storage of Adverse events commonly associated with human insulin insulin formulations. insulin. Patients should be informed that frequent, patient- therapy include the following: DR. CONANT Glucose monitoring is recommended for all patients performed blood glucose measurements are needed to achieve Body as Whole: allergic reactions (see PRECAUTIONS, Allergy). with diabetes. effective glycemic control to avoid both hyperglycemia and Skin and Appendages: lipodystrophy, pruritus, rash. Mild LEVEMIR is not to be used in insulin infusion pumps. hypoglycemia. Patients must be instructed on handling of placebo and active treatment groups in special situations such as intercurrent conditions (illness, stress, injection site reactions occurred more frequently with LEVEMIR Any change of insulin dose should be made cautiously or emotional disturbances), an inadequate or skipped insulin than with NPH human insulin and usually resolved in a few days progression to a full outbreak. “The prob- and only under medical supervision. Changes in insulin dose, inadvertent administration of an increased insulin dose, to a few weeks (see PRECAUTIONS, Allergy). strength, timing of dosing, manufacturer, type (e.g., regular, lem is, when you say you’re having a pro- inadequate food intake, or skipped meals. Refer patients to the Other: NPH, or insulin analogs), species (animal, human), or LEVEMIR “Patient Information” circular for additional information. method of manufacture (rDNA versus animal-source insulin) Hypoglycemia: (see WARNINGS and PRECAUTIONS). drome, are you really having an eruption may result in the need for a change in dosage. Concomitant As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycemia or hyperglycemia. In trials of up to 6 months duration in patients with type 1 and or not? You can’t really tell that,” said Dr. oral antidiabetic treatment may need to be adjusted. , the incidence of severe hypoglycemia with PRECAUTIONS Patients with diabetes should be advised to inform their health LEVEMIR was comparable to the incidence with NPH, and, as Conant, professor of dermatology at the General care professional if they are pregnant or are contemplating expected, greater overall in patients with type 1 diabetes (Table 4). pregnancy (see PRECAUTIONS, Pregnancy). University of California, San Francisco. Inadequate dosing or discontinuation of treatment may lead to : hyperglycemia and, in patients with type 1 diabetes, diabetic Laboratory Tests In trials of up to 6 months duration in patients with type 1 The challenge for physicians is to con- . The first symptoms of hyperglycemia usually occur As with all insulin therapy, the therapeutic response to LEVEMIR and type 2 diabetes, LEVEMIR was associated with somewhat gradually over a period of hours or days. They include nausea, should be monitored by periodic blood glucose tests. Periodic less weight gain than NPH (Table 4). Whether these observed vince patients to keep 1,500 mg of famci- vomiting, drowsiness, flushed dry skin, dry mouth, increased measurement of HbA is recommended for the monitoring of 1c differences represent true differences in the effects of LEVEMIR clovir with them at all times so they can , thirst and loss of appetite as well as acetone breath. long-term glycemic control. and NPH insulin is not known, since these trials were not Untreated hyperglycemic events are potentially fatal. Drug Interactions blinded and the protocols (e.g., diet and exercise instructions take it immediately. Women tend to keep LEVEMIR is not intended for intravenous or intramuscular A number of substances affect glucose metabolism and may require and monitoring) were not specifically directed at exploring administration. The prolonged duration of activity of insulin insulin dose adjustment and particularly close monitoring. hypotheses related to weight effects of the treatments the 3-tablet 1,500-mg dose in their purses, detemir is dependent on injection into subcutaneous tissue. compared. The clinical significance of the observed differences The following are examples of substances that may reduce Intravenous administration of the usual subcutaneous has not been established. but men tend to think it will be fine if they the blood-glucose-lowering effect of insulin: corticosteroids, dose could result in severe hypoglycemia. Absorption after danazol, diuretics, sympathomimetic agents (e.g., epinephrine, Table 4: Safety Information on Clinical Studies intramuscular administration is both faster and more extensive wait until they get home, Dr. Conant said. albuterol, terbutaline), isoniazid, phenothiazine derivatives, than absorption after subcutaneous administration. Weight (kg) Hypoglycemia somatropin, hormones, estrogens, progestogens (e.g., (events/subject/month) “Herpes is like a punch in the nose. If LEVEMIR should not be diluted or mixed with any other in oral contraceptives). Treatment #of Baseline Endof Major* Minor** insulin preparations (see PRECAUTIONS, Mixing of Insulins). subjects treatment someone is going to hit you and you step The following are examples of substances that may increase Insulin may cause sodium retention and edema, particularly if the blood-glucose-lowering effect of insulin and susceptibility Type 1 aside, you’re not going to have a black eye. previously poor metabolic control is improved by intensified to hypoglycemia: oral antidiabetic drugs, ACE inhibitors, Study A LEVEMIR N=276 75.0 75.1 0.045 2.184 insulin therapy. disopyramide, fibrates, fluoxetine, MAO inhibitors, propoxyphene, NPH N=133 75.7 76.4 0.035 3.063 If you don’t move away, you’re going to salicylates, somatostatin analog (e.g., octreotide), and Study C LEVEMIR N=492 76.5 76.3 0.029 2.397 Lipodystrophy and are among potential clinical NPH N=257 76.1 76.5 0.027 2.564 have a black eye for about a week,” he said. adverse effects associated with the use of all insulins. sulfonamide antibiotics. Study D LEVEMIR N=232 N/A N/A 0.076 2.677 A second Novartis-sponsored study As with all insulin preparations, the time course of LEVEMIR Beta-blockers, clonidine, lithium salts, and alcohol may either Pediatric NPH N=115 N/A N/A 0.083 3.203 potentiate or weaken the blood-glucose-lowering effect of action may vary in different individuals or at different times in Type 2 showed that genital herpes lesions could be the same individual and is dependent on site of injection, blood insulin. Pentamidine may cause hypoglycemia, which may Study E LEVEMIR N=237 82.7 83.7 0.001 0.306 supply, temperature, and physical activity. sometimes be followed by hyperglycemia. In addition, under NPH N=239 82.4 85.2 0.006 0.595 halted at the papule stage in about one of the influence of sympatholytic medicinal products such as Study F LEVEMIR N=195 81.8 82.3 0.003 0.193 Adjustment of dosage of any insulin may be necessary if patients beta-blockers, clonidine, guanethidine, and reserpine, the signs NPH N=200 79.6 80.9 0.006 0.235 every four patients taking 1,000 mg of fam- change their physical activity or their usual meal plan. of hypoglycemia may be reduced or absent. Hypoglycemia in-vitro in-vivo * Major = requires assistance of another individual because of neurologic ciclovir in divided doses during the first day The results of and protein binding studies impairment As with all insulin preparations, hypoglycemic reactions may be demonstrate that there is no clinically relevant interaction between ** Minor = plasma glucose <56 mg/dl, subject able to deal with the they recognized prodromal symptoms. associated with the administration of LEVEMIR. Hypoglycemia and fatty acids or other protein bound drugs. episode him/herself is the most common adverse effect of insulins. Early warning In that study, led by Dr. Stephen Tyring symptoms of hypoglycemia may be different or less pronounced Mixing of Insulins OVERDOSAGE under certain conditions, such as long duration of diabetes, If LEVEMIR is mixed with other insulin preparations, the profile Hypoglycemia may occur as a result of an excess of insulin of the University of Texas Health Science diabetic nerve , use of medications such as beta-blockers, of action of one or both individual components may change. relative to food intake, energy expenditure, or both. Mild or intensified diabetes control (see PRECAUTIONS, Drug Mixing LEVEMIR with , a rapid acting insulin episodes of hypoglycemia usually can be treated with oral Center in Houston, patient-initiated thera- analog, resulted in about 40% reduction in AUC and C glucose. Adjustments in drug dosage, meal patterns, or exercise Interactions). Such situations may result in severe hypoglycemia (0-2h) max py reduced by 2 days the healing time of le- (and, possibly, loss of consciousness) prior to patients’ awareness for insulin aspart compared to separate injections when the may be needed. More severe episodes with coma, seizure, or of hypoglycemia. ratio of insulin aspart to LEVEMIR was less than 50%. neurologic impairment may be treated with intramuscular/ subcutaneous or concentrated intravenous glucose. sions in 163 patients receiving active drug, LEVEMIR should NOT be mixed or diluted with any other The time of occurrence of hypoglycemia depends on the action After apparent clinical recovery from hypoglycemia, continued insulin preparations. compared with 166 receiving placebo. profile of the insulins used and may, therefore, change when the observation and additional intake may be treatment regimen or timing of dosing is changed. In patients Carcinogenicity, Mutagenicity, Impairment of Fertility necessary to avoid reoccurrence of hypoglycemia. More than 30% of subjects in the active being switched from other intermediate or long-acting insulin Standard 2-year carcinogenicity studies in animals have not preparations to once- or twice-daily LEVEMIR, dosages can be been performed. Insulin detemir tested negative for genotoxic More detailed information is available on request. treatment arm developed no lesions or prescribed on a unit-to-unit basis; however, as with all insulin potential in the in-vitro reverse mutation study in bacteria, Rx only preparations, dose and timing of administration may need to be only papules after initiating therapy, vs. human peripheral blood lymphocyte chromosome aberration Date of issue: October 19, 2005 adjusted to reduce the risk of hypoglycemia. test, and the in-vivo mouse micronucleus test. Manufactured For Novo Nordisk Inc., Princeton, NJ 08540 about 10% of patients in the placebo group. Renal Impairment Pregnancy: Teratogenic Effects: Pregnancy Category C As with other insulins, the requirements for LEVEMIR may need In a fertility and embryonic development study, insulin detemir Manufactured By Novo Nordisk A/S, 2880 Bagsvaerd, Denmark In this study,patients obtained skin sam- to be adjusted in patients with renal impairment. was administered to female rats before mating, during mating, www.novonordisk-us.com and throughout pregnancy at doses up to 300 nmol/kg/day ples for polymerase chain reaction testing Hepatic Impairment Levemir® and Novo Nordisk® are trademarks of Novo Nordisk A/S. As with other insulins, the requirements for LEVEMIR may need (3 times the recommended human dose, based on plasma Area and visited the clinic for 3 consecutive days to be adjusted in patients with hepatic impairment. Under the Curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day © 2006 Novo Nordisk Inc. 130128 March 2006 produced numbers of litters with visceral anomalies. Doses up to following symptoms and up to 14 days or Injection Site and Allergic Reactions 900 nmol/kg/day (approximately 135 times the recommended As with any insulin therapy, lipodystrophy may occur at the human dose based on AUC ratio) were given to rabbits during total healing if lesions developed. The re- injection site and delay insulin absorption. Other injection site organogenesis. Drug-dose related increases in the incidence of reactions with insulin therapy may include redness, pain, itching, fetuses with gall bladder abnormalities such as small, bilobed, searchers concluded that famciclovir could , swelling, and inflammation. Continuous rotation of the bifurcated and missing gall bladders were observed at a dose of reduce healing time as well as prevent de- injection site within a given area may help to reduce or prevent 900 nmol/kg/day. The rat and rabbit embryofetal development these reactions. Reactions usually resolve in a few days to a few studies that included concurrent human insulin control groups velopment and/or progression of lesions in some patients with a history of recur- rent genital herpes outbreaks. ■

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