Tolinase Diabetes Type 2 Treatment - Tolazamide Patient Information

Tolinase, tolazamide full prescribing information

What side effects may occur with Tolinase?

Side effects cannot be anticipated. If any appear or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Tolinase. The most frequently encountered side effects from Tolinase—nausea, a full, bloated feeling, and heartburn—may disappear if the dosage is reduced.

Hives, itching, and rash may appear initially and then disappear as you continue to take the drug. If a skin reaction persists, you should stop taking Tolinase.

Why should Tolinase not be prescribed?

Do not take Tolinase if you are sensitive to it or have ever had an allergic reaction to it; if you are suffering from diabetic ketoacidosis (a chemical imbalance leading to nausea, vomiting, confusion, and coma); or if you have type 1 (insulin-dependent) diabetes and are not taking insulin.

Special warnings about Tolinase

It's possible that drugs such as Tolinase may lead to more heart problems than diet treatment alone, or diet plus insulin. If you have a heart condition, you may want to discuss this with your doctor.

Like other oral antidiabetic drugs, Tolinase may produce severe low blood sugar (hypoglycemia) if the dosing is wrong. While taking Tolinase, you are particularly susceptible to episodes of low blood sugar if:

You suffer from a kidney or liver problem;
You have a lack of adrenal or pituitary hormones; or
You are older, run-down, or malnourished.
You are at increased risk for a low blood sugar episode if you are hungry, exercising heavily, drinking alcohol, or using more than one glucose-lowering drug.

Note that an episode of low blood sugar may be difficult to recognize if you are an older person or if you are taking a beta-blocker drug (Inderal, Lopressor, Tenormin, and others).

If switching to Tolinase from chlorpropamide (Diabinese), you should take special care to avoid an episode of low blood sugar.

Stress such as fever, trauma, infection, or surgery may increase blood sugar to the point that you require insulin injections.

Possible food and drug interactions when taking Tolinase

If Tolinase is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Tolinase with the following:

Airway-opening drugs such as Sudafed and Ventolin
Alcohol
Aspirin or related drugs
Beta-blocking blood pressure medications such as Inderal and Lopressor
Blood-thinning drugs such as Coumadin
Calcium channel blockers such as Calan and Isoptin
Chloramphenicol (Chloromycetin)
Corticosteroids such as Cortef, Decadron, and Medrol
Diuretics such as Esidrix and Diuril
Estrogens such as Premarin and Estraderm
Isoniazid (Nydrazid)
MAO inhibitors (antidepressants such as Nardil and Parnate)
Miconazole (Monistat)
Nicotinic acid
Nonsteroidal anti-inflammatory drugs such as Motrin and Naprosyn
Oral contraceptives
Phenothiazines (antipsychotic drugs such as Mellaril)
Phenytoin (Dilantin)
Probenecid
Rifampin (Rifadin)
Sulfa drugs such as Bactrim and Gantrisin
Thyroid drugs such as Synthroid

Special information if you are pregnant or breastfeeding

If you are pregnant or plan to become pregnant, inform your doctor immediately. Tolinase is not recommended for use during pregnancy, and should not be prescribed if you might become pregnant while taking it.

Control of diabetes during pregnancy is very important, but in most cases it should be accomplished with insulin injections rather than oral antidiabetic drugs.

Tolinase should not be used during breastfeeding because of possible harmful effects on the baby. If you are a new mother, you may need to choose between taking Tolinase and breastfeeding your baby.

Recommended dosage for Tolinase

Your doctor will determine the dosage level based on your needs.

Adults

The usual starting dose of Tolinase tablets for the mild to moderately severe type 2 diabetic is 100 to 150 milligrams daily taken with breakfast or the first main meal.

Older Adults

If you are malnourished, underweight, an older person, or not eating properly, the initial dose is usually 100 milligrams once a day. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia (low blood sugar). If you do not stick to your prescribed dietary regimen, you are more likely to have an unsatisfactory response to Tolinase.

Overdosage

An overdose of Tolinase can cause an episode of low blood sugar. Mild low blood sugar without loss of consciousness should be treated with oral glucose, an adjusted meal pattern, and possibly a reduction in the Tolinase dosage. Severe low blood sugar, which may cause coma or seizures, is a medical emergency and must be treated in a hospital. If you suspect an overdose of Tolinase, seek medical attention immediately.

last updated: 04/2006

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

APA Reference
Staff, H. (2006, April 30). Tolinase Diabetes Type 2 Treatment - Tolazamide Patient Information, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/diabetes/medications/tolinase-tolazamide-diabetic-treatment

Last Updated: July 21, 2014

Tolinase for Treatment of Diabetes - Tolinase Full Prescribing Information

HealthyPlace.com Staff Writer

Brand name: Tolinase
Generic Name: Tolazamide

Description

Tolinase Tablets contain tolazamide, an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide is a white or creamy-white powder with a melting point of 165° to 173° C. The solubility of tolazamide at pH 6.0 (mean urinary pH) is 27.8 mg per 100 mL.

The chemical names for tolazamide are (1) Benzenesulfonamide, N-[[(hexahydro-1H-azepin-1-yl) amino] carbonyl]-4-methyl-; (2) 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea and its molecular weight is 311.40. The structural formula is represented below:

Tolinase structural formula

Tolinase Tablets for oral administration are available as scored, white tablets containing 100 mg, 250 mg or 500 mg tolazamide. Inactive ingredients: calcium sulfate, docusate sodium, magnesium stearate, methylcellulose, sodium alginate.

Clinical Pharmacology

Actions

Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Some patients who are initially responsive to oral hypoglycemic drugs, including Tolinase Tablets, may become unresponsive or poorly responsive over time. Alternatively, Tolinase Tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs.

In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance.

Pharmacokinetics

Tolazamide is rapidly and well absorbed from the gastrointestinal tract. Peak serum concentrations occur at three to four hours following a single oral dose of the drug. The average biological half-life of the drug is seven hours. The drug does not continue to accumulate in the blood after the first four to six doses are administered. A steady or equilibrium state is reached during which the peak and nadir values do not change from day to day after the fourth to sixth doses.

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0-70%. They are excreted principally in the urine. Following a single oral dose of tritiated tolazamide, 85% of the dose was excreted in the urine and 7% in the feces over a five-day period. Most of the urinary excretion of the drug occurred within the first 24 hours post administration.

When normal fasting nondiabetic subjects are given a single 500 mg dose of tolazamide orally, a hypoglycemic effect can be noted within 20 minutes after ingestion with a peak hypoglycemic effect occurring in two to four hours. Following a single oral dose of 500 mg tolazamide, a statistically significant hypoglycemic effect was demonstrated in fasted nondiabetic subjects 20 hours after administration. With fasting diabetic patients, the peak hypoglycemic effect occurs at four to six hours. The duration of maximal hypoglycemic effect in fed diabetic patients is about ten hours, with the onset occurring at four to six hours and with the blood glucose levels beginning to rise at 14 to 16 hours. Single dose potency of tolazamide in normal subjects has been shown to be 6.7 times that of tolbutamide on a milligram basis. Clinical experience in diabetic patients has demonstrated tolazamide to be approximately five times more potent than tolbutamide on a milligram basis, and approximately equivalent in milligram potency to chlorpropamide.

Indications and Usage

Tolinase Tablets are indicated as an adjunct to diet to lower the blood glucose in patients with noninsulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone.

In initiating treatment for noninsulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed and cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of Tolinase must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient thus requiring only short-term administration of Tolinase.

During maintenance programs, Tolinase should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of Tolinase in asymptomatic patients, it should be recognized that controlling the blood glucose in noninsulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.

Contraindications

Tolinase Tablets are contraindicated in patients with: 1) known hypersensitivity or allergy to Tolinase; 2) diabetic ketoacidosis, with or without coma. This condition should be treated with insulin; 3) Type I diabetes, as sole therapy.

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with noninsulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (DIABETES, 19 (supp. 2):747-830, 1970.)

UGDP reported that patients treated for five to eight years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 ½ times that of patients with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of Tolinase and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Precautions

General

Hypoglycemia

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of tolazamide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, loss of control of blood glucose may occur. At such times it may be necessary to discontinue Tolinase Tablets and administer insulin.

The effectiveness of any hypoglycemic drug, including Tolinase, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Information for Patients

Patients should be informed of the potential risks and advantages of Tolinase and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Laboratory Tests

Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin may be useful in some patients.

Drug Interactions

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving Tolinase, the patient should be closely observed for hypoglycemia. When such drugs are withdrawn from a patient receiving Tolinase, the patient should be observed closely for loss of control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Tolinase, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Tolinase, the patient should be observed closely for hypoglycemia.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Carcinogenicity

In a bioassay for carcinogenicity, rats and mice of both sexes were treated with tolazamide for 103 weeks at low and high doses. No evidence of carcinogenicity was found.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Tolinase, administered to pregnant rats at ten times the human dose, decreased litter size but did not produce teratogenic effects in the offspring. In rats treated at a daily dose of 14 mg/kg no reproductive aberrations or drug related fetal anomalies were noted. At an elevated dose of 100 mg/kg per day there was a reduction in the number of pups born and an increased perinatal mortality. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tolinase is not recommended for the treatment of the pregnant diabetic patient. Serious consideration should also be given to the possible hazards of the use of Tolinase in women of child bearing age and in those who might become pregnant while using the drug.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nonteratogenic Effects

Prolonged severe hypoglycemia (four to ten days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If Tolinase is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether tolazamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insufficiency,which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

Adverse Reactions

Tolinase Tablets have generally been well tolerated. In clinical studies in which more than 1,784 diabetic patients were specifically evaluated for incidence of side effects, only 2.1% were discontinued from therapy because of side effects.

Hypoglycemia

See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal Reactions

Cholestatic jaundice may occur rarely; Tolinase Tablets should be discontinued if this occurs. Gastrointestinal disturbances, eg, nausea, epigastric fullness, and heartburn, are the most common reactions and occurred in 1% of patients treated during clinical trials. They tend to be dose-related and may disappear when dosage is reduced.

Dermatologic Reactions

Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in 0.4% of patients treated during clinical trials. These may be transient and may disappear despite continued use of Tolinase; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, disulfiram-like reactions with Tolinase have been reported very rarely.

Cases of hyponatremia have been reported with tolazamide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Miscellaneous

Weakness, fatigue, dizziness, vertigo, malaise and headache were reported infrequently in patients treated during clinical trials. The relationship to therapy with Tolinase is difficult to assess.

Overdosage

Overdosage of sulfonylureas, including Tolinase Tablets, can produce hypoglycemia.

Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustment in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is suspected or diagnosed, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dl. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

Dosage and Administration

There is no fixed dosage regimen for the management of diabetes mellitus with Tolinase Tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of Tolinase may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose

The usual starting dose of Tolinase Tablets for the mild to moderately severe Type II diabetic patient is 100-250 mg daily administered with breakfast or the first main meal. Generally, if the fasting blood glucose is less than 200 mg/dl, the starting dose is 100 mg/day as a single daily dose. If the fasting blood glucose value is greater than 200 mg/dl, the starting dose is 250 mg/day as a single dose. If the patient is malnourished, underweight, elderly, or not eating properly, the initial therapy should be 100 mg once a day. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimen are more prone to exhibit unsatisfactory response to drug therapy.

Transfer From Other Hypoglycemic Therapy

Patients Receiving Other Oral Antidiabetic Therapy

Transfer of patients from other oral antidiabetes regimens to Tolinase should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to Tolinase, no transition period or initial or priming dose is necessary. When transferring from chlorpropamide, particular care should be exercised to avoid hypoglycemia.

Tolbutamide

If receiving less than 1 gm/day, begin at 100 mg of tolazamide per day. If receiving 1 gm or more per day, initiate at 250 mg of tolazamide per day as a single dose.

Chlorpropamide

250 mg of chlorpropamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of tolazamide. The patient should be observed carefully for hypoglycemia during the transition period from chlorpropamide to Tolinase (one to two weeks) due to the prolonged retention of chlorpropamide in the body and the possibility of a subsequent overlapping drug effect.

Acetohexamide

100 mg of tolazamide may be considered to provide approximately the same degree of blood glucose control as 250 mg of acetohexamide.

Patients Receiving Insulin

Some Type II diabetic patients who have been treated only with insulin may respond satisfactorily to therapy with Tolinase. If the patient's previous insulin dosage has been less than 20 units, substitution of 100 mg of tolazamide per day as a single daily dose may be tried. If the previous insulin dosage was less than 40 units, but more than 20 units, the patient should be placed directly on 250 mg of tolazamide per day as a single dose. If the previous insulin dosage was greater than 40 units, the insulin dosage should be decreased by 50% and 250 mg of tolazamide per day started. The dosage of Tolinase should be adjusted weekly (or more often in the group previously requiring more than 40 units of insulin).

During this conversion period when both insulin and Tolinase are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.

Maximum Dose

Daily doses of greater than 1000 mg are not recommended. Patients will generally have no further response to doses larger than this.

Usual Maintenance Dose

The usual maintenance dose is in the range of 100-1000 mg/day with the average maintenance dose being 250-500 mg/day. Following initiation of therapy, dosage adjustment is made in increments of 100 mg to 250 mg at weekly intervals based on the patient's blood glucose response.

Dosage Interval

Once a day therapy is usually satisfactory. Doses up to 500 mg/day should be given as a single dose in the morning. 500 mg once daily is as effective as 250 mg twice daily. When a dose of more than 500 mg/day is required, the dose may be divided and given twice daily.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section).

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

How is Supplied

Tolinase Tablets are available in the following strengths and package sizes:

100 mg (white, round, scored, imprinted Tolinase 100)

Unit-of-Use Bottles of 100 NDC 0009-0070-02

250 mg (white, round, scored, imprinted Tolinase 250)

Bottles of 200 NDC 0009-0114-04

Bottles of 1000 NDC 0009-0114-02

Unit-of-Use Bottles of 100 NDC 0009-0114-05

500 mg (white, round, scored, imprinted Tolinase 500)

Unit-of-Use Bottles of 100 NDC 0009-0477-06

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Rx only

Pfizer

Tolazamide patient information (in plain English)

last updated: 04/2006

The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

APA Reference
Staff, H. (2006, April 30). Tolinase for Treatment of Diabetes - Tolinase Full Prescribing Information, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/diabetes/medications/tolinase-diabetic-treatment-prescribing-information

Last Updated: March 11, 2016

Lantus for Treatment of Diabetes - Lantus Full Prescribing Information

HealthyPlace.com Staff Writer

Brand Name: Lantus
Generic Name: insulin glargine

Dosage Form: Injection (Lantus must NOT be diluted or mixed with any other insulin or solution)

Description

Lantus® (insulin glargine [rDNA origin] injection) is a sterile solution of insulin glargine for use as an injection. Insulin glargine is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose-lowering agent. (See CLINICAL PHARMACOLOGY). Lantus is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, it is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and a molecular weight of 6063. It has the following structural formula:

Insulin Structural Formula

Lantus consists of insulin glargine dissolved in a clear aqueous fluid. Each milliliter of Lantus (insulin glargine injection) contains 100 IU (3.6378 mg) insulin glargine.

Inactive ingredients for the 10 mL vial are 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.

Inactive ingredients for the 3 mL cartridge are 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. Lantus has a pH of approximately 4.

Clinical Pharmacology

Mechanism of Action

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Pharmacodynamics

Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At pH 4, as in the Lantus injection solution, it is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a patient's basal insulin.

In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as human insulin. In euglycemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous insulin glargine was slower than NPH human insulin. The effect profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH human insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

Figure 1. Activity Profile in Patients with Type 1 Diabetesâ€

Activity Profile in Patients with Type 1 Diabetes

*Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values); indicative of insulin activity.

â€ Between-patient variability (CV, coefficient of variation); insulin glargine, 84% and NPH, 78%.

The longer duration of action (up to 24 hours) of Lantus is directly related to its slower rate of absorption and supports once-daily subcutaneous administration. The time course of action of insulins, including Lantus, may vary between individuals and/or within the same individual.

Pharmacokinetics

Absorption and Bioavailability

After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH human insulin. Serum insulin concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.

After subcutaneous injection of 0.3 IU/kg insulin glargine in patients with type 1 diabetes, a relatively constant concentration/time profile has been demonstrated. The duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar.

Metabolism

A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

Special Populations

Age, Race, and Gender

Information on the effect of age, race, and gender on the pharmacokinetics of Lantus is not available. However, in controlled clinical trials in adults (n=3890) and a controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between insulin glargine and NPH human insulin.

Smoking

The effect of smoking on the pharmacokinetics/pharmacodynamics of Lantus has not been studied.

Pregnancy

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Lantus has not been studied (see PRECAUTIONS, Pregnancy).

Obesity

In controlled clinical trials, which included patients with Body Mass Index (BMI) up to and including 49.6 kg/m2, subgroup analyses based on BMI did not show any differences in safety and efficacy between insulin glargine and NPH human insulin.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of Lantus has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including Lantus, may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Lantus has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including Lantus, may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).

Clinical Studies

The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH human insulin in open-label, randomized, active-control, parallel studies of 2327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1563 adult patients with type 2 diabetes mellitus (see Tables 1-3). In general, the reduction in glycated hemoglobin (HbA1c) with Lantus was similar to that with NPH human insulin. The overall rates of hypoglycemia did not differ between patients with diabetes treated to Lantus compared with NPH human insulin.

Type 1 Diabetes-Adult (see Table 1).

In two large, randomized, controlled clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to basal-bolus treatment with Lantus once daily at bedtime or to NPH human insulin once or twice daily and treated for 28 weeks. Regular human insulin was administered before each meal. Lantus was administered at bedtime. NPH human insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily. In one large, randomized, controlled clinical study (Study C), patients with type 1 diabetes (n=619) were treated for 16 weeks with a basal-bolus insulin regimen where insulin lispro was used before each meal. Lantus was administered once daily at bedtime and NPH human insulin was administered once or twice daily. In these studies, Lantus and NPH human insulin had a similar effect on glycohemoglobin with a similar overall rate of hypoglycemia.

Table 1: Type 1 Diabetes Mellitus-Adult

	Study A		Study B		Study C
Treatment duration	28 weeks		28 weeks		16 weeks
Treatment in combination with	Regular insulin		Regular insulin		Insulin lispro
	Lantus	NPH	Lantus	NPH	Lantus	NPH
Number of subjects treated	292	293	264	270	310	309
HbA1c
Endstudy mean	8.13	8.07	7.55	7.49	7.53	7.60
Adj. mean change from baseline	+0.21	+0.10	-0.16	-0.21	-0.07	-0.08
Lantus - NPH	+0.11		+0.05		+0.01
95% CI for Treatment difference	(-0.03; +0.24)		(-0.08; +0.19)		(-0.11; +0.13)
Basal insulin dose
Endstudy mean	19.2	22.8	24.8	31.3	23.9	29.2
Mean change from baseline	-1.7	-0.3	-4.1	+1.8	-4.5	+0.9
Total insulin dose
Endstudy mean	46.7	51.7	50.3	54.8	47.4	50.7
Mean change from baseline	-1.1	-0.1	+0.3	+3.7	-2.9	+0.3
Fasting blood glucose (mg/dL)
Endstudy mean	146.3	150.8	147.8	154.4	144.4	161.3
Adj. mean change from baseline	-21.1	-16.0	-20.2	-16.9	-29.3	-11.9

Type 1 Diabetes-Pediatric (see Table 2).

In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Lantus was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohemoglobin and the incidence of hypoglycemia were observed in both treatment groups.

Table 2: Type 1 Diabetes Mellitus-Pediatric

	Study D
Treatment duration	28 weeks
Treatment in combination with	Regular insulin
	Lantus	NPH
Number of subjects treated	174	175
HbA1c
Endstudy mean	8.91	9.18
Adj. mean change from baseline	+0.28	+0.27
Lantus - NPH	+0.01
95% CI for Treatment difference	(-0.24; +0.26)
Basal insulin dose
Endstudy mean	18.2	21.1
Mean change from baseline	-1.3	+2.4
Total insulin dose
Endstudy mean	45.0	46.0
Mean change from baseline	+1.9	+3.4
Fasting blood glucose (mg/dL)
Endstudy mean	171.9	182.7
Adj. mean change from baseline	-23.2	-12.2

Type 2 Diabetes-Adult (see Table 3).

In a large, randomized, controlled clinical study (Study E) (n=570), Lantus was evaluated for 52 weeks as part of a regimen of combination therapy with insulin and oral antidiabetes agents (a sulfonylurea, metformin, acarbose, or combinations of these drugs). Lantus administered once daily at bedtime was as effective as NPH human insulin administered once daily at bedtime in reducing glycohemoglobin and fasting glucose. There was a low rate of hypoglycemia that was similar in Lantus and NPH human insulin treated patients. In a large, randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetes agents (n=518), a basal-bolus regimen of Lantus once daily at bedtime or NPH human insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals as needed. Lantus had similar effectiveness as either once- or twice-daily NPH human insulin in reducing glycohemoglobin and fasting glucose with a similar incidence of hypoglycemia.

Table 3: Type 2 Diabetes Mellitus-Adult

	Study E		Study F
Treatment duration	52 weeks		28 weeks
Treatment in combination with	Oral agents		Regular insulin
	Lantus	NPH	Lantus	NPH
Number of subjects treated	289	281	259	259
HbA1c
Endstudy mean	8.51	8.47	8.14	7.96
Adj. mean change from baseline	-0.46	-0.38	-0.41	-0.59
Lantus - NPH	-0.08		+0.17
95% CI for Treatment difference	(-0.28; +0.12)		(-0.00; +0.35)
Basal insulin dose
Endstudy mean	25.9	23.6	42.9	52.5
Mean change from baseline	+11.5	+9.0	-1.2	+7.0
Total insulin dose
Endstudy mean	25.9	23.6	74.3	80.0
Mean change from baseline	+11.5	+9.0	+10.0	+13.1
Fasting blood glucose (mg/dL)
Endstudy mean	126.9	129.4	141.5	144.5
Adj. mean change from baseline	-49.0	-46.3	-23.8	-21.6

Lantus Flexible Daily Dosing

The safety and efficacy of Lantus administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a large, randomized, controlled clinical study, in patients with type 1 diabetes (study G, n=378). Patients were also treated with insulin lispro at mealtime. Lantus administered at different times of the day resulted in similar reductions in glycated hemoglobin compared to that with bedtime administration (see Table 4). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose level was observed just prior to injection of Lantus regardless of time of administration, i.e. pre-breakfast, pre-dinner, or bedtime.

In this study, 5% of patients in the Lantus-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. Routine monitoring during this trial revealed the following mean changes in systolic blood pressure: pre-breakfast group, 1.9 mm Hg; pre-dinner group, 0.7 mm Hg; pre-bedtime group, -2.0 mm Hg.

The safety and efficacy of Lantus administered pre-breakfast or at bedtime were also evaluated in a large, randomized, active-controlled clinical study (Study H, n=697) in type 2 diabetes patients no longer adequately controlled on oral agent therapy. All patients in this study also received AMARYL® (glimepiride) 3 mg daily. Lantus given before breakfast was at least as effective in lowering glycated hemoglobin A1c (HbA1c) as Lantus given at bedtime or NPH human insulin given at bedtime (see Table 4).

Table 4: Flexible Lantus Daily Dosing in Type 1 (Study G) and Type 2 (Study H) Diabetes Mellitus

	Study G			Study H
Treatmentduration	24 weeks			24 weeks
Treatment in combination with:	Insulin lispro			AMARYL® (glimepiride)
	Lantus Breakfast	Lantus Dinner	Lantus Bedtime	Lantus Breakfast	Lantus Bedtime	NPH Bedtime
*Intent to treat â€ Not applicable
Number of subjects treated*	112	124	128	234	226	227
HbA1c
Baseline mean	7.56	7.53	7.61	9.13	9.07	9.09
Endstudy mean	7.39	7.42	7.57	7.87	8.12	8.27
Mean change from baseline	-0.17	-0.11	-0.04	-1.26	-0.95	-0.83
Basal insulin dose (IU)
Endstudy mean	27.3	24.6	22.8	40.4	38.5	36.8
Mean change from baseline	5.0	1.8	1.5
Total insulin dose (IU)				NAâ€	NA	NA
Endstudy mean	53.3	54.7	51.5
Mean change from baseline	1.6	3.0	2.3

Indications and Usage

Lantus is indicated for once-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.

Contraindications

Lantus is contraindicated in patients hypersensitive to insulin glargine or the excipients.

Warnings

Hypoglycemia is the most common adverse effect of insulin, including Lantus. 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, timing of dosing, manufacturer, type (e.g., regular, NPH, or insulin analogs), species (animal, human), or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage. Concomitant oral antidiabetes treatment may need to be adjusted.

Precautions

General

Lantus is not intended for intravenous administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia.

Lantus must NOT be diluted or mixed with any other insulin or solution. If Lantus is diluted or mixed, the solution may become cloudy, and the pharmacokinetic/pharmacodynamic profile (e.g., onset of action, time to peak effect) of Lantus and/or the mixed insulin may be altered in an unpredictable manner. When Lantus and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and time to maximum effect for regular human insulin was observed. The total bioavailability of the mixture was also slightly decreased compared to separate injections of Lantus and regular human insulin. The relevance of these observations in dogs to humans is not known.

As with all insulin preparations, the time course of Lantus action may vary in different individuals or at different times in the same individual and the rate of absorption is dependent on blood supply, temperature, and physical activity.

Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Hypoglycemia

As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Lantus. Hypoglycemia is the most common adverse effect of insulins. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetes nerve disease, use of medications such as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions). Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients' awareness of hypoglycemia.

The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may, therefore, change when the treatment regimen or timing of dosing is changed. Patients being switched from twice daily NPH insulin to once-daily Lantus should have their initial Lantus dose reduced by 20% from the previous total daily NPH dose to reduce the risk of hypoglycemia (see DOSAGE AND ADMINISTRATION, Changeover to Lantus).

The prolonged effect of subcutaneous Lantus may delay recovery from hypoglycemia.

In a clinical study, symptoms of hypoglycemia or counterregulatory hormone responses were similar after intravenous insulin glargine and regular human insulin both in healthy subjects and patients with type 1 diabetes.

Renal Impairment

Although studies have not been performed in patients with diabetes and renal impairment, Lantus requirements may be diminished because of reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations).

Hepatic Impairment

Although studies have not been performed in patients with diabetes and hepatic impairment, Lantus requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations).

Injection Site and Allergic Reactions

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy include redness, pain, itching, hives, swelling, and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Most minor reactions to insulins usually resolve in a few days to a few weeks.

Reports of injection site pain were more frequent with Lantus than NPH human insulin (2.7% insulin glargine versus 0.7% NPH). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy.

Immediate-type allergic reactions are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalized skin reactions, angioedema, bronchospasm, hypotension, or shock and may be life threatening.

Intercurrent Conditions

Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress.

Information for Patients

Lantus must only be used if the solution is clear and colorless with no particles visible (see DOSAGE AND ADMINISTRATION, Preparation and Handling).

Patients must be advised that Lantus must NOT be diluted or mixed with any other insulin or solution (see PRECAUTIONS, General).

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and hypoglycemia and hyperglycemia management. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, or skipped meals. Refer patients to the Lantus "Patient Information" circular for additional information.

As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycemia or hyperglycemia.

Patients with diabetes should be advised to inform their health care professional if they are pregnant or are contemplating pregnancy.

Drug Interactions

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetes products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.

The following are examples of substances that may reduce the blood-glucose-lowering effect of insulin: corticosteroids, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which is for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2. The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown.

Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2, maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH human insulin.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. The drug was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2. In rabbits, doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

There are no well-controlled clinical studies of the use of insulin glargine in pregnant women. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in such patients. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is unknown whether insulin glargine is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Lantus is administered to a nursing woman. Lactating women may require adjustments in insulin dose and diet.

Pediatric Use

Safety and effectiveness of Lantus have been established in the age group 6 to 15 years with type 1 diabetes.

Geriatric Use

In controlled clinical studies comparing insulin glargine to NPH human insulin, 593 of 3890 patients with type 1 and type 2 diabetes were 65 years and older. The only difference in safety or effectiveness in this subpopulation compared to the entire study population was an expected higher incidence of cardiovascular events in both insulin glargine and NPH human insulin-treated patients.

In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS, Hypoglycemia).

Adverse Reactions

The adverse events commonly associated with Lantus include the following:

Body as a whole: allergic reactions (see PRECAUTIONS).

Skin and appendages: injection site reaction, lipodystrophy, pruritus, rash (see PRECAUTIONS).

Other: hypoglycemia (see WARNINGS and PRECAUTIONS).

In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in Lantus-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy. Other treatment-emergent injection site reactions occurred at similar incidences with both insulin glargine and NPH human insulin.

Retinopathy was evaluated in the clinical studies by means of retinal adverse events reported and fundus photography. The numbers of retinal adverse events reported for Lantus and NPH treatment groups were similar for patients with type 1 and type 2 diabetes. Progression of retinopathy was investigated by fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Study (ETDRS). In one clinical study involving patients with type 2 diabetes, a difference in the number of subjects with â‰¥3-step progression in ETDRS scale over a 6-month period was noted by fundus photography (7.5% in Lantus group versus 2.7% in NPH treated group). The overall relevance of this isolated finding cannot be determined due to the small number of patients involved, the short follow-up period, and the fact that this finding was not observed in other clinical studies.

Overdose

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes long-term and life-threatening hypoglycemia. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.

More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia.

Dosage and Administration

Lantus is a recombinant human insulin analog. Its potency is approximately the same as human insulin. It exhibits a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing.

Lantus may be administered at any time during the day. Lantus should be administered subcutaneously once a day at the same time every day. For patients adjusting timing of dosing with Lantus, see WARNINGS and PRECAUTIONS, Hypoglycemia. Lantus is not intended for intravenous administration (see PRECAUTIONS). Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. The desired blood glucose levels as well as the doses and timing of antidiabetes medications must be determined individually. Blood glucose monitoring is recommended for all patients with diabetes. The prolonged duration of activity of Lantus is dependent on injection into subcutaneous space.

As with all insulins, injection sites within an injection area (abdomen, thigh, or deltoid) must be rotated from one injection to the next.

In clinical studies, there was no relevant difference in insulin glargine absorption after abdominal, deltoid, or thigh subcutaneous administration. As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables.

Lantus is not the insulin of choice for the treatment of diabetes ketoacidosis. Intravenous short-acting insulin is the preferred treatment.

Pediatric Use

Lantus can be safely administered to pediatric patients â‰¥6 years of age. Administration to pediatric patients

Initiation of Lantus Therapy

In a clinical study with insulin naÃ¯ve patients with type 2 diabetes already treated with oral antidiabetes drugs, Lantus was started at an average dose of 10 IU once daily, and subsequently adjusted according to the patient's need to a total daily dose ranging from 2 to 100 IU.

Changeover to Lantus

If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with Lantus, the amount and timing of short-acting insulin or fast-acting insulin analog or the dose of any oral antidiabetes drug may need to be adjusted. In clinical studies, when patients were transferred from once-daily NPH human insulin or ultralente human insulin to once-daily Lantus, the initial dose was usually not changed. However, when patients were transferred from twice-daily NPH human insulin to Lantus once daily, to reduce the risk of hypoglycemia, the initial dose (IU) was usually reduced by approximately 20% (compared to total daily IU of NPH human insulin) and then adjusted based on patient response (see PRECAUTIONS, Hypoglycemia).

A program of close metabolic monitoring under medical supervision is recommended during transfer and in the initial weeks thereafter. The amount and timing of short-acting insulin or fast-acting insulin analog may need to be adjusted. This is particularly true for patients with acquired antibodies to human insulin needing high-insulin doses and occurs with all insulin analogs. Dose adjustment of Lantus and other insulins or oral antidiabetes drugs may be required; for example, if the patient's timing of dosing, weight or lifestyle changes, or other circumstances arise that increase susceptibility to hypoglycemia or hyperglycemia (see PRECAUTIONS, Hypoglycemia).

The dose may also have to be adjusted during intercurrent illness (see PRECAUTIONS, Intercurrent Conditions).

Preparation and Handling

Parenteral drug products should be inspected visually prior to administration whenever the solution and the container permit. Lantus must only be used if the solution is clear and colorless with no particles visible.

Mixing and diluting: Lantus must NOT be diluted or mixed with any other insulin or solution (see PRECAUTIONS, General).

Vial: The syringes must not contain any other medicinal product or residue.

Cartridge system: If OptiClik®, the Insulin Delivery Device for Lantus, malfunctions, Lantus may be drawn from the cartridge system into a U-100 syringe and injected.

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

How is Supplied

Lantus 100 units per mL (U-100) is available in the following package size:

10 mL vials (NDC 0088-2220-33)

3 mL cartridge system¹, package of 5 (NDC 0088-2220-52)

¹Cartridge systems are for use only in OptiClik® (Insulin Delivery Device)

Storage

Unopened Vial/Cartridge system

Unopened Lantus vials and cartridge systems should be stored in a refrigerator, 36°F - 46°F (2°C - 8°C). Lantus should not be stored in the freezer and it should not be allowed to freeze.

Discard if it has been frozen.

Open (In-Use) Vial/Cartridge system

Opened vials, whether or not refrigerated, must be used within 28 days after the first use. They must be discarded if not used within 28 days. If refrigeration is not possible, the open vial can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 86°F (30°C).

The opened (in-use) cartridge system in OptiClik® should NOT be refrigerated but should be kept at room temperature (below 86°F [30°C]) away from direct heat and light. The opened (in-use) cartridge system in OptiClik® kept at room temperature must be discarded after 28 days. Do not store OptiClik®, with or without cartridge system, in a refrigerator at any time.

Lantus should not be stored in the freezer and it should not be allowed to freeze. Discard if it has been frozen.

These storage conditions are summarized in the following table:

	Not in-use (unopened) Refrigerated	Not in-use (unopened) Room Temperature	In-use (opened) (See Temperature Below)
10 mL Vial	Until expiration date	28 days	28 days Refrigerated or room temperature
3 mL Cartridge system	Until expiration date	28 days	28 days Refrigerated or room temperature
3 mL Cartridge system inserted into OptiClik®			28 days Room temperature only (Do not refrigerate)

Manufactured for an distributed by:

sanofi-aventis U.S. LLC
Bridgewater NJ 08807

Made in Germany

www.Lantus.com

OptiClik® is a registered trademark of sanofi-aventis U.S. LLC, Bridgewater NJ 08807

last updated 04/2006

Lantus, insulin glargine (rDNA origin), patient information (in plain English)

Lantus, OptiClik, Solostar Pen, full prescribing information

APA Reference
Staff, H. (2006, April 30). Lantus for Treatment of Diabetes - Lantus Full Prescribing Information, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/diabetes/medications/lantus-glargine-insulin-treatment

Last Updated: March 10, 2016

Lantus Diabetes Treatment - Lantus Patient Information

HealthyPlace.com Staff Writer

Brand Names: Lantus, Lantus OptiClik Cartridge, Lantus Solostar Pen
Generic Name: insulin glargine

Pronounced: (IN soo lin GLAR jeen)

What is Lantus and why is Lantus prescribed?

Lantus (insulin glargine) is a man-made form of a natural hormone. It is a long-acting insulin that is slightly different from other forms of insulin that are not man-made and it works by lowering levels of glucose in the blood.

Lantus is used to treat type 1 (insulin-dependent) or type 2 (non insulin-dependent) diabetes.

Lantus may also be used for other purposes not listed.

Important information about Lantus

Do not use Lantus if you are allergic to insulin glargine.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Lantus is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Before using Lantus

Do not use Lantus if you are allergic to insulin glargine.

Before using Lantus, tell your doctor if you have liver or kidney disease.

Tell your doctor about all other medications you use, including any oral (by mouth) diabetes medications.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether Lantus passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Lantus, OptiClik, Solostar Pen, full prescribing information

How should I use Lantus?

Use Lantus exactly as it was prescribed for you. Do not use it in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

You should not mix Lantus with other insulins.

Lantus is given as an injection (shot) under your skin. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject this medicine. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

Lantus should be thin, clear, and colorless. Do not use the medication if it has changed colors or has any particles in it. Call your doctor for a new prescription.

Choose a different place in your injection skin area each time you use Lantus. Do not inject into the same place two times in a row.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

The SoloStar injection pen contains a total of 300 units of insulin. The pen is designed to deliver from 1 to 80 units with each press of the injection button. Do not press the button more than one time per injection unless your doctor has prescribed a dose greater than 80 units.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, or skip meals. These things can affect your glucose levels and your Lantus insulin dose needs may also change.

Watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your Lantus insulin doses if needed.

Ask your doctor how to adjust your Lantus dose if needed. Do not change your dose without first talking to your doctor. Carry an ID card or wear a medical alert bracelet stating that you have diabetes, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are diabetic. Storing unopened vials, OptiClik, or SoloStar devices: Keep in the carton and store in a refrigerator, protected from light. Throw away any insulin not used before the expiration date on the medicine label. Store the injection pen with its cap on. Unopened vials, OptiClik, or SoloStar devices may also be stored at room temperature for up to 28 days, away from heat and bright light. Throw away any insulin not used within 28 days.

Storing after your first use: You may keep "in-use" vials or cartridges not yet loaded into the OptiClik in the refrigerator or at room temperature, protected from light. Use within 28 days.

Do not refrigerate an in-use OptiClik or SoloStar device, or a cartridge that has been inserted into the OptiClik. Keep it at room temperature and use within 28 days.

Do not freeze Lantus, and throw away the medication if it has become frozen.

What happens if I miss a dose?

Use the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose. You should not use more than one dose in a 24-hour period unless your doctor tells you to.

It is important to keep Lantus on hand at all times. Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An insulin overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, seizure (convulsions), or coma.

What should I avoid while using Lantus?

Do not change the brand of insulin glargine or syringe you are using without first talking to your doctor or pharmacist. Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using Lantus. Do not expose Lantus to high heat.

Lantus side effects

Get emergency medical help if you have any of these signs of insulin allergy: itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out.

Hypoglycemia, or low blood sugar, is the most common side effect of Lantus. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, trouble concentrating, confusion, or seizure (convulsions). Watch for signs of low blood sugar. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar.

Tell your doctor if you have itching, swelling, redness, or thickening of the skin where you inject Lantus.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lantus?

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

albuterol (Proventil, Ventolin);
clonidine (Catapres);
reserpine;
guanethidine (Ismelin); or
beta-blockers such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), timolol (Blocadren) and others.

There are many other medicines that can increase or decrease the effects of Lantus on lowering your blood sugar. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Where can I get more information?

Your pharmacist can provide more information about Lantus.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Lantus only for the indication prescribed.

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

last updated 04/2006

APA Reference
Staff, H. (2006, April 28). Lantus Diabetes Treatment - Lantus Patient Information, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/diabetes/medications/lantus-glargine-insulin-pump

Last Updated: July 21, 2014

Helicopter Parents: 25% of Parents are Overly Involved, Say College Students; Experience, Inc. Polls College Students about Parental Involvement

HealthyPlace.com Staff Writer

Experience, Inc., the leading provider of career services to students and alumni, today announced the findings from a recent online poll of more than 400 hovering over their children, or 'helic students and recent graduates regarding the growing trend of parentsopter parents.'

While the overwhelming majority of students describe their parents as moderately involved, 25% of them responded that their parents were "overly involved to the point that their involvement was either annoying or embarrassing." Conversely, 13% of the respondents said their parents were not involved at all.

"This is a time when students are setting out on their own," said Zi Teng Wang, a freshman at Washington University in St. Louis. "For example, my father threw me a Fortune magazine with the 'Top 500' companies and told me to just send a resume to every one on the list. He called it an internship search, which was very frustrating. Parents mean well, but anxiety from being separated from their children can drive them to grab onto the steering wheel and never let go."

Thirty-eight percent of students admitted that their parents had either called into, or physically attended meetings with academic advisors, and 31% of students reported that their parents had called professors to complain about a grade. But the ties run strong on both sides: 65% of young adults still seek counsel from their parents on their academic and career paths.

Survey Methodology

Experience's "Helicopter Parents" online poll was completed on January 11, 2006. Students who visited Experience.com were invited to participate in the poll, and over 400 of them voluntarily completed the survey.

APA Reference
Staff, H. (2006, January 24). Helicopter Parents: 25% of Parents are Overly Involved, Say College Students; Experience, Inc. Polls College Students about Parental Involvement, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/parenting/news/helicopter-parents-25-of-parents-are-overly-involved-say-college-students-experience-inc-polls-college-students-about-parental-involvement

Last Updated: May 29, 2019

How Therapy Helps Anxiety Disorders

HealthyPlace.com Staff Writer

Psychotherapy is an effective treatment for anxiety disorders. Read how therapy helps anxiety disorders sufferers.

Role of Psychotherapy in Effective Treatment of Anxiety

Everyone feels anxious and under stress from time-to-time. Situations such as meeting tight deadlines, important social obligations or driving in heavy traffic, often bring about anxious feelings. Such mild anxiety may help make you alert and focused on facing threatening or challenging circumstances. On the other hand, anxiety disorders cause severe distress over a period of time and disrupt the lives of individuals suffering from them. The frequency and intensity of anxiety involved in these disorders is often debilitating. But fortunately, with proper and effective treatment, people suffering from anxiety disorders can lead normal lives.

What are the major kinds of anxiety disorders?
Why is it important to seek treatment for these anxiety disorders?
Are there effective treatments available for anxiety disorders?
How can a qualified therapist help someone suffering from an anxiety disorder?
How long does psychological treatment take?

What are the major kinds of anxiety disorders?

There are several major types of anxiety disorders, each with its own characteristics.

People with generalized anxiety disorder have recurring fears or worries, such as about health or finances, and they often have a persistent sense that something bad is just about to happen. The reason for the intense feelings of anxiety may be difficult to identify. But the fears and worries are very real and often keep individuals from concentrating on daily tasks.
Panic disorder involves sudden, intense and unprovoked feelings of terror and dread. People who suffer from this disorder generally develop strong fears about when and where their next panic attack will occur, and they often restrict their activities as a result.
A related disorder involves phobias, or intense fears, about certain objects or situations. Specific phobias may involve things such as encountering certain animals or fear of flying in airplanes, whereas social phobias involve fear of social settings or public places.
Obsessive-compulsive disorder is characterized by persistent, uncontrollable and unwanted feelings or thoughts (obsessions) and routines or rituals in which individuals engage to try to prevent or rid themselves of these thoughts (compulsions). Examples of common compulsions include washing hands or cleaning house excessively for fear of germs, or checking over something repeatedly for errors.
Someone who suffers severe physical or emotional trauma such as from a natural disaster or serious accident or crime may experience post-traumatic stress disorder. Thoughts, feelings and behavior patterns become seriously affected by reminders of the event, sometimes months or even years after the traumatic experience. Symptoms such as shortness of breath, racing heartbeat, trembling and dizziness often accompany certain anxiety disorders such as panic and generalized anxiety disorders. Although they may begin at any time, anxiety disorders often surface in adolescence or early adulthood. There is some evidence of a genetic or family predisposition to certain anxiety disorders.

Why is it important to seek treatment for these disorders?

If left untreated, anxiety disorders can have severe consequences. For example, some people who suffer from recurring panic attacks avoid at all costs putting themselves in a situation that they fear may trigger another panic attack. Such avoidance behavior may create problems by conflicting with job requirements, family obligations or other basic activities of daily living.

Many people who suffer from an untreated anxiety disorder are prone to other psychological disorders, such as depression, and they have a greater tendency to abuse alcohol and other drugs. Their relationships with family members, friends and coworkers may become very strained. And their job performance may falter.

Are there effective treatments available for anxiety disorders?

Absolutely. Most cases of anxiety disorder can be treated successfully by appropriately trained health and mental health care professionals.

According to the National Institute of Mental Health, research has demonstrated that both 'behavioral therapy' and 'cognitive therapy' can be highly effective in treating anxiety disorders. Behavioral therapy involves using techniques to reduce or stop the undesired behavior associated with these disorders. For example, one approach involves training patients in relaxation and deep breathing techniques to counteract the agitation and hyperventilation (rapid, shallow breathing) that accompany certain anxiety disorders.

Through cognitive therapy, patients learn to understand how their thoughts contribute to the symptoms of anxiety disorders, and how to change those thought patterns to reduce the likelihood of occurrence and the intensity of reaction. The patient's increased cognitive awareness is often combined with behavioral techniques to help the individual gradually confront and tolerate fearful situations in a controlled, safe environment.

Proper and effective anti-anxiety medications may have a role in treatment along with psychotherapy. In cases where medications are used, the patient's care may be managed collaboratively by a therapist and physician. It is important for patients to realize that there are side effects to any drugs, which must be monitored closely by the prescribing physician.

How can a qualified therapist help someone suffering from an anxiety disorder?

Licensed psychologists are highly qualified to diagnose and treat anxiety disorders. Individuals suffering from these disorders should seek a provider who is competent in cognitive and behavioral therapies. Experienced mental health professionals have the added benefit of having helped other patients recover from anxiety disorders.

Family psychotherapy and group psychotherapy (typically involving individuals who are not related to one another) offer helpful approaches to treatment for some patients with anxiety disorders. In addition, mental health clinics or other specialized treatment programs dealing with specific disorders such as panic or phobias may also be available nearby.

How long does psychological treatment take?

It is very important to understand that treatments for anxiety disorders do not work instantly. The patient should be comfortable from the outset with the general treatment being proposed and with the therapist with whom he or she is working. The patient's cooperation is crucial, and there must be a strong sense that the patient and therapist are collaborating as a team to remedy the anxiety disorder.

No one plan works well for all patients. Treatment needs to be tailored to the needs of the patient and to the type of disorder, or disorders, from which the individual suffers. A therapist and patient should work together to assess whether a treatment plan seems to be on track. Adjustments to the plan sometimes are necessary, since patients respond differently to treatment.

Many patients will begin to improve noticeably within eight to ten sessions, especially those who carefully follow the outlined treatment plan.

There is no question that the various kinds of anxiety disorders can severely impair a person's functioning in work, family and social environments. But the prospects for long-term recovery for most individuals who seek appropriate professional help are very good. Those who suffer from anxiety disorders can work with a qualified and experienced therapist such as a licensed psychologist to help them regain control of their feelings and thoughts -- and their lives.

Source: American Psychological Assoc., October 1998

next: Monoamine Oxidase Inhibitors (MAOIs) for Social Anxiety Disorder
~ anxiety-panic library articles
~ all anxiety disorders articles

APA Reference
Staff, H. (2005, December 29). How Therapy Helps Anxiety Disorders, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/anxiety-panic/articles/how-therapy-helps-anxiety-disorders

Last Updated: July 2, 2016

Brain Damage From Bipolar Disorder

HealthyPlace.com Staff Writer

If you have a broken leg, you can tell people you have a fracture in your left tibia. If you have a bad heart you can let people know you have a weak aortic valve. But what do you say if you have a mood disorder? Most of us settle for the explanation that we have a chemical imbalance, which is about as satisfactory as your mechanic handing you a bill with this one item: "Engine Imbalance."

Then there is the matter of collateral damage. We know depression can stop the brain it its tracks while mania runs it off the rails, with corresponding deficits in our ability to think and reason, but we are led to believe these are only temporary occurrences, right? Maybe not.

If only a mood disorder were just a mood disorder. A lengthy review article by Carrie Bearden PhD et al of the University of Pennsylvania published in Bipolar Disorders cites "findings of persistent neuropsychological deficits" in long-term bipolar patients, even when tested in symptom-free states. The relationship between these deficits and length of illness led the authors to suggest that "episodes of depression and mania may exact damage to learning and memory systems."

An article by FC Murphy PhD and BJ Sahakian PhD of Cambridge University in the British Journal of Psychiatry draws a similar conclusion: "The balance of evidence ... supports a hypothesis of residual cognitive impairments."

Father Time appears to be a major factor. Dr Bearden et al cite a study that found that chronic, multiple-episode patients exhibited more severe cognitive impairment than younger patients or patients who remit, and that these impairments were not restricted to their affective episodes. The same study found 40 percent of the patients were rapid-cyclers. Another study found that of 25 patients initially hospitalized with mania with no signs of cognitive impairment, one third showed significant cognitive impairment five to seven years later.

There is always the possibility that the meds are responsible. One long-term study found lithium users (one-third who had a university degree) to be in the low average range on functions of attention and memory. Nevertheless, the authors believe that while medication may cause some degree of cognitive slowing, our pills are not the main culprit.

Studies results suggest that episodes of depression and mania may exact damage to learning and memory systems. Bearden et al's review of what could be wrong with the brain reads like a neurologist's laundry list from hell: ventricular enlargements, cortical atrophy, cerebellar vermal atrophy, white matter hypertensities (especially in the frontal cortex and basal ganglia structures), greater left temporal lobe volume, increased amygdala volume, enlarged right hippocampal volume, hypoplasmia of the medial temporal lobe, and more. Then there's the matter of those chemical imbalances, such as glucose metabolism and phospholipid metabolism.

Say all that in rap time and you have the sound of our brains breaking down, no longer capable of processing information the way it is supposed to. It is possible that these studies did not adequately account for the normal aging process, as Dr Bearden was ready to acknowledge to this writer, but she also added that it is "likely that there is an interaction between the disease process and normal aging processes, such that people affected with bipolar illness are somehow more vulnerable to the effects of aging."

Lest we cause a panic, Dr Bearden wants to remind readers that "while these brain differences are there, they are subtle. They are certainly not present in all people with bipolar illness, nor do we really know what there functional significance may be in any given individual. And most likely if a radiologist were to take a glance at a brain scan of a person with bipolar disorder, it would look normal - it's just when you actually measure things quantitatively that you find differences. I realize that sometimes these research findings can sound really horrific, and I don't want to cause anyone undue concern."

Also, it appears that our current bipolar medications actually repair and protect brain cells, which is one of the better arguments for staying compliant. Further research in this area may produce new drugs with enhanced neuroprotective properties.

One day, perhaps, brain doctors will be able to open up the hood and do a valve job. Researchers at the Salk Institute of Biological Studies isolated stem cells from the hippocampus of adult rats and modified the gene to produce glowing proteins, which were cloned and took on the properties of adult neurons as they matured, including the ability in some to make synaptic connections with other neurons. Alzheimer's and Parkinson's come most immediately to mind in the context of this type of research, but a mood application can't be far beyond that, assuming they can get the technology to work in humans, which is a very big if. In the meantime, there is hope, which we may have to suffice for the next decade or two.

next: UCLA-led Study Challenges Bipolar Depression Treatment Guidelines
~ bipolar disorder library
~ all bipolar disorder articles

APA Reference
Staff, H. (2005, December 1). Brain Damage From Bipolar Disorder, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/bipolar-disorder/articles/brain-damage-from-bipolar-disorder

Last Updated: April 7, 2017

What We Know About Sex

HealthyPlace.com Staff Writer

USA WEEKEND Magazine and the world-famous Kinsey Institute team up for a special report to the nation. Topic: the most important things science has learned about sex. We've come a long way, baby.

A ubiquitous topic that no one likes to discuss. A highly private act that catches the public eye. Sublime. Dangerous. Compelling. Confusing. The most fundamental of human experiences, and the one responsible for the perpetuation our species. Sex.

In recent decades, America's sexual landscape has been rearranged by forces including new forms of contraception, skyrocketing divorce rates, a sea change in women's societal roles and an explosion of graphic media imagery. Even the idea of what constitutes sex -- think Bill Clinton and Monica Lewinsky -- has changed.

Today, USA WEEKEND Magazine teams up with the Kinsey Institute for Research in Sex, Gender and Reproduction to assess America's sexual health and understanding. The Indiana University-based research institute has created headlines for more than 50 years, ever since biologist Alfred Kinsey published "Sexual Behavior in the Human Male" and "Sexual Behavior in the Human Female" -- collectively known as the Kinsey reports. These landmark volumes shed the first scientific light on once-taboo topics, such as homosexuality, premarital sex and masturbation. The institute (kinseyinstitute.org) has continued to study human sexuality and has become the world's foremost repository of information about sex.

Sort through it all, says noted sex researcher and psychiatrist John Bancroft, M.D., director of the Kinsey Institute since 1995, and "the United States is in a mess, as far as sex is concerned." For instance, nearly half of all pregnancies are unintended, with 835,000 teenage pregnancies annually; they are said to cost the United States as much as $15 billion a year.

Research into human sexuality could help improve these dismal numbers, as well as unravel significant medical and psychological mysteries, Bancroft says. Unfortunately, societal discomfort about sex marginalizes -- and sometimes condemns -- scientific sex research. As a result, he concedes, "It's difficult to think of any important aspect of the human condition about which we know less."

Nonetheless, sex researchers have made progress in psychological and physiological fields. Below is Bancroft's list of today's most important findings on sex.

Sexuality defines our lives. Sexuality is central to all of us -- even people who aren't sexually active. "It's absolutely fundamental to the organization of human society and has been from the earliest history," Bancroft says.

Studies show that sexuality plays a significant role in our self-esteem and emotional well-being. "For most people, what they think about themselves as a sexual person is a very important part of how they think about themselves as a human being," Bancroft explains. "The effect of having a good sexual relationship on one's well-being is very substantial." A 2000 Kinsey survey found that general physical and mental health were strongly correlated to sexual well-being and satisfaction. Poor health tended to increase sexual problems and decrease desire.

There's no "normal." Decades of scientific inquiry have made clear that sexuality exists on a continuum: No two people are exactly the same in their level of sexual interest, patterns of response or interests. And because of this variability, there really is no such thing as a "normal" frequency of sexual activity or a "normal" number of fantasies. "What is right for two people in a relationship is what works for them," Bancroft says.

Women and men have different needs. Kinsey was one of the first to question the assumption that female sexuality has the same basis as male sexuality; his findings showed that only a minority of women achieve orgasm through intercourse alone. Continued research has demonstrated the complexity of women's sexuality. A 2003 Kinsey study found that the quality of women's emotional interaction with their partner during sex proved more important than the physical aspects, such as orgasm, in determining sexual satisfaction.

Intimacy becomes more important with age. Although sexual interest and the ease of sexual response tend to decrease with age, the quality of the sexual relationship need not deteriorate. In an AARP survey of close to 1,400 adults over 45, two out of three of those with partners said they were extremely or somewhat satisfied with their sex lives. "Provided both partners can be open with each other, the importance of their sexual relationship may shift in emphasis from shared pleasure to shared intimacy," Bancroft says. Unfortunately, normal changes associated with aging -- especially men's inability to achieve consistent erections -- often are misinterpreted as a relationship failure.

Help has been found for male dysfunction. About 5% to 10% of men under 50 have erection problems due to a host of medical and psychological conditions, a number that increases sharply with age. Compared with some of the very unwieldy treatment methods that have evolved over the past 20 years, including penile implants and injections, the introduction of Viagra and drugs like it has been revolutionary. "Although it's not without side effects, it's available, it works for most people, and there wasn't anything like it there before," Bancroft says. Meanwhile, there's a push to find an equivalent drug for women, a search complicated by the fact that genital response is far less central to women's experience than erections are to men's. Low sexual interest is the most commonly reported sexual problem in women; researchers are trying to determine how often it is hormonally based.

Orientation isn't a choice. Research shows most people become aware of their sexual orientation around puberty and perhaps as early as age 10. Findings such as the discovery of the so-called gay gene have shown that genetics play a role in determining why a minority of people end up with a same-sex orientation, but Bancroft holds that genes are "just part of the picture. There are far more questions than answers."

Being ill -- and taking medicine -- can cause sexual problems. Many common medical conditions, such as depression and high blood pressure, can cause sexual problems. One of the downsides to modern medicine, however, is that the medications used to treat those conditions also can negatively impact sexual functioning. And although Bancroft says he was pushed aside when he tried to research this issue in the 1970s, it has been taken more seriously in the medical community recently.

The 2003 Kinsey study found that negative side effects on sex and mood were the most likely reason for women to discontinue oral contraceptives -- sexual impairment was cited by 86% of women who discontinued. "This is an important aspect of women's reproductive health that has not received the attention that it should from the medical profession and the pharmaceutical industry," Bancroft says.

The media create sexual expectations. The publication of Kinsey's work 50 years ago generated a crush of media coverage. "There was shock sometimes, and horror sometimes, and amazement at how much people were doing [sexually]," Bancroft says. "Now there seems to be a preoccupation with how little people are doing."

Indeed, recently headlines have screamed that Americans are sex-starved. But Bancroft isn't so sure there's any scientific substance behind the hype. "We haven't got any clear evidence that this is the case, but that doesn't seem to deter [the media]." The reality of our sex lives is probably far less dramatic than the media would have us believe.

Technology transforms sex lives. When photography became widely available at the end of the 19th century, it soon was put to use to provide erotic images. More recently, the Internet has been both a boon and a menace to healthy sexuality. Although it provides access to very personalized information and can serve as a means of support and connection for those whose sexuality makes them feel isolated, others are unable to resist the lure of interactive Internet pornography, a fact Bancroft deems "quite scary."

Because an extraordinary variety of sexual stimuli is accessible in relatively private settings, he maintains that Internet erotica is potentially far more dangerous than traditional print or video sources and can interfere with relationships and work performance while emptying bank accounts. The National Council on Sex Addiction and Compulsivity estimates that a staggering 2 million Americans are addicted to cybersex.

Description
Pharmacology
Indications and Usage
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Warnings
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Information for Patients

4 ways to improve America's sexual health

John Bancroft, M.D., director of the Kinsey Institute, provides his prescription for a healthier society.

Eradicate the sexual double standard. "Until we have achieved a society in which sexual responsibility is equally shared by men and women, from early adolescence onward, we will continue to have major social as well as personal problems associated with sex."

Teach sexual responsibility to young people. "The expectation is that young people will spend their years of maximum sexual arousability in a society that bombards them constantly with sexual messages in a state of 'suspended sexuality.' It does not help to deny information to adolescents when they are experiencing sexual feelings. It is also not possible to teach our youth to behave in a responsible manner without being open and honest about sex."

Respect all varieties of sexual expression, as long as they are handled responsibly. Sexual responsibility, Bancroft says, means protecting against disease and unwanted pregnancy, avoiding causing physical or psychological harm to ourselves and our partners, participating only in truly consensual sex and avoiding sexual exploitation of those too young to make responsible decisions.

Encourage trust. Being sexual means letting go. Feeling safe to do so with a partner has a powerful bonding effect. Conversely, many sexual problems result from not feeling safe or from being hurt while vulnerable.

Kinsey, the movie

The historic, sometimes demonized work of Alfred Kinsey is coming to the big screen. "Kinsey", starring Liam Neeson, is expected in theaters next fall.

"He's a really fascinating, complicated guy," says writer-director Bill Condon, who wrote the screenplay for the Academy Award winner "Chicago", "but the thing that makes it compelling is that the questions he raised are still relevant."

The Kinsey Institute is not formally involved in the production but made materials --including personal scrapbooks and letters -- available to the filmmakers.

Condon is "bracing for controversy" surrounding the film, but don't expect anything too heavy: "It's about sex, so it can't help but be funny."

Sex by the numbers ...

We're monogamous in marriage

Women: more than 80%

Men: 65% to 85%

We think about sex ...

Every day:

Men, 54%;
Women, 19%

A few times a month/week:

Men, 43%;
Women, 67%

Less than once a month:

Men, 4%;
Women, 14%

Frequency of sex

Ages 18-29: Average 112 times a year

Ages 30-39: Average 86 times a year

Ages 40-49: Average 69 times a year

Contraception

90% of sexually active women and their partners use contraception, although not always consistently or correctly. Sexually transmitted diseases 15 million new cases a year

Cover photograph by Simon Watson, Getty Images.

next: Guidelines for Diagnosis and Treatment of Sexual Dysfunction

APA Reference
Staff, H. (2005, November 1). What We Know About Sex, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/sex/main/what-we-know-about-sex

Last Updated: August 21, 2014

How Sex Problems Can Destroy A Relationship

HealthyPlace.com Staff Writer

When your partner has no interest in sex despite your best efforts, it's easy to become perplexed. And without guidance, partners may characterize the problem in ways that can destroy the relationship.

Sex: What Problem?

Kelly seemed to have it all. A loving mother of three and a public-relations executive in Manhattan, she had a handsome and charming partner who was a successful entrepreneur. They jetted off for vacations in the Caribbean and dined in the finest restaurants. But their relationship floundered in one intractable area.

"After a while," Kelly says, "he just stopped wanting to have sex. He'd go months without even touching me."

It's a subject that's full of shame: low sex drive. When your partner has no interest in sex despite your best efforts, it's easy to become perplexed. And without guidance, partners may characterize the problem in ways that can destroy the relationship.

In a society saturated with sexual imagery, it seems strange that some people have no desire for sex. But it is a startlingly common problem. Millions of people suffer from a condition known as hypoactive sexual desire (HSD), about 25 percent of all Americans, by one estimate, or a third of women and a fifth of men. Sex researchers and therapists now recognize it as the most common sexual problem.

In recent years, experts have turned their attention to the causes of low sexual desire, and sex therapists are working on strategies to treat it. Although there is a 50 percent positive outcome in treatment of hypoactive sexual desire, many of those who have HSD don't seek help. This is usually because they don't realize it's a problem, other issues in the relationship seem more important or they feel ashamed.

Many couples in conflict may have an underlying problem with sexual desire. When desire fades in one partner, other things start to fall apart.

How little is too little?

For Pam, happily married and in her forties, her once healthy sexual desire simply disappeared about six months ago. "I don't know what has happened to my sexual appetite," she says, "but it is like someone turned it off at the switch." She and her husband still have sex, maybe once every few weeks, but she does it out of obligation, not enthusiasm.

"I used to enjoy sex," Pam says. "Now there's a vital part of me that's missing."

Ordinary people aren't in a constant state of sexual desire. Everyday occurrences "fatigue, job stress, even the common cold" can drive away urges for lovemaking. Usually, however, spending romantic time with a partner, having sexual thoughts or seeing stimulating images can lead to arousal and the return of a healthy sex drive.

Yet for some people, desire never returns, or was never there to begin with. Frequently, even healthy sexual fantasies are virtually nonexistent in some people who suffer from HSD.

Just how little sex is too little? Sometimes, when a partner complains of not having enough sex, his problem may actually be an unusually high sex drive. Experts agree that there is no daily minimum requirement of sexual activity. In a British survey, published in the Journal of Sex and Marital Therapy, 24 percent of couples reported having no sex in the previous three months. And the classic study, Sex in America, found that one-third of couples had sex just a few times a year. Although the studies report frequency of sex, not desire, it's likely that one partner in these couples has HSD.

One tiny pill

Years ago, another sexual problem "erectile dysfunction" received a sudden burst of attention when a medical "cure" hit the shelves. Before Viagra came along, men with physically based problems suffered impotence in silence, and without much hope. Now many couples enjoy a renewed reservoir of passion.

Obviously, any pill that relieves hypoactive sexual desire would be wildly popular. Unfortunately, the causes of HSD seem to be complex and varied; some sufferers might be treated with a simple pill, but most will likely need therapy -- not chemistry.

One common source of reduced sexual desire is the use of antidepressants known as selective serotonin reuptake inhibitors. SSRIs have been found to all but eliminate desire in some patients. Antidepressants such as Prozac (Fluoxetine) and are among the most widely prescribed drugs for treating depression. Yet one distressing side effect is a drop in sex drive. Some studies indicate that as many as 50 percent of people on SSRIs suffer from a markedly reduced sex drive.

Researchers believe that SSRIs quash the libido by flooding the bloodstream with serotonin, a chemical that signals satiety. "The more you bathe people in serotonin, the less they need to be sexual," says Joseph Marzucco, MSPAC, a sex therapist practicing in Portland, Oregon. "SSRIs can just devastate sexual desire."

Fortunately, researchers are studying antidepressants that act through other channels. Bupropion hydrochloride (Wellbutrin), which enhances the brain's production of the neurotransmitters dopamine and norepinephrine, has received extra attention as a substitute for SSRIs. Early studies suggest that it may actually increase sexual desire in test subjects. A study reported last year in the Journal of Sex and Marital Therapy found that nearly one-third of participants who took bupropion reported more desire, arousal and fantasy.

It's all in your head

Physiological problems can also lead to a loss of sexual desire. Men with abnormal pituitary glands can overproduce the hormone prolactin, which usually turns off the sex drive. As reported in the International Journal of Impotence Research, tests of a drug that blocks prolactin found it increased the libido in healthy males.

In women, some experts believe that one cause of weak sexual desire is, ironically, low testosterone levels. Normally associated with brawny, deep-voiced men, testosterone is a hormone with a definite masculine identity. But women also make small amounts of it in their ovaries, and it plays an important role in their sexual lives. Without a healthy level of testosterone in the blood, some researchers believe, women are unable to properly respond to sexual stimuli. Furthermore, there is anecdotal evidence that testosterone supplements can restore the sex drive in women.

Rosemary Basson, M.D., of the Vancouver Hospital and Health Sciences Center in British Columbia, however, cautions that too little is known about the role testosterone plays in women. "We don't even know how much testosterone is normal," Basson says. "The tests designed for men can't pick up the levels found in women."

In one study suggesting that HSD is more psychological than physiological, Basson and her colleagues tested the effects of Viagra on women who reported arousal problems. Basson found that while the drug generally produced the physical signals of sexual arousal, many women reported that they still didn't feel turned on.

Indeed, many psychologists and sex therapists believe that most patients with HSD have sound bodies and troubled relationships. The clinical experience of Weeks has shown that two factors identified in a relationship can, over time, devastate the sex drive: chronically suppressed anger toward the partner and a lack, or loss, of control over the relationship. And once these issues threaten a healthy sex drive, lack of intimacy can aggravate the problems further. Without help, these issues can balloon until the relationship itself is seriously damaged. And, consequently, HSD becomes further entrenched.

Lacking the desire for desire

Although hypoactive sexual desire is one of the most difficult to address of all sexual problems, it can be treated successfully. The key is to find a highly qualified sex and marital therapist who has experience in dealing with it. Unfortunately, while HSD is the most common problem that sex therapists see, millions of cases go untreated.

Some people who lack desire are just too embarrassed to seek help, especially men. Others are so focused on immediate concerns -- such as a stressful job or a family crisis, that they put off dealing with the loss of a healthy libido. Still others have become so used to having no sex drive that they no longer miss it; they lack the desire for desire. These people represent the most severe cases, the hardest to treat.

Some people who don't get treatment find ways to adjust. "Thank goodness my husband is so patient and caring," Pam says. "He tries to spark interest, but when it is not ignited he'll settle for cuddling and caressing."

Other relationships can't survive the strain. After a year, Kelly and her boyfriend broke up. "I couldn't convince him that it was a problem," she says, "but it was."

Gerald Weeks, Ph.D., A.B.S., is a professor of counseling at the University of Nevada in Las Vegas and a board certified sex therapist of the American Board of Sexology. Jeffrey Winters, formerly with Discover magazine, is a science writer based in New York.

APA Reference
Staff, H. (2005, November 1). How Sex Problems Can Destroy A Relationship, HealthyPlace. Retrieved on 2024, December 18 from https://www.healthyplace.com/sex/main/sex-problems-can-destroy-a-relationship

Last Updated: June 25, 2019

GlucaGen for Diabetics - GlucaGen Full Prescribing Information

HealthyPlace.com Staff Writer

Brand Name: GlucaGen
Generic Name: Glucagon Hydrochloride

Contents:

GlucaGen, glucagon hydrochloride, patient information (in plain English)

Description

GlucaGen^® (glucagon [rDNA origin] for injection) manufactured by Novo Nordisk A/S is produced by expression of recombinant DNA in a Saccharomyces cerevisiae vector with subsequent purification.

The chemical structure of the glucagon in GlucaGen^® is identical to naturally occurring human glucagon and to glucagon extracted from beef and pork pancreas. Glucagon with the empirical formula of C₁₅₃H₂₂₅N₄₃O₄₉S, and a molecular weight of 3483, is a single-chain polypeptide containing 29 amino acid residues. The structure of glucagon is:

Structure of Glucagon

GlucaGen^® 1 mg (1 unit) is supplied as a sterile, lyophilized white powder in a 2 ml vial, alone, or accompanied by Sterile Water for Reconstitution (1 ml) also in a 2 ml vial (10 pack or diagnostic kit). It is also supplied as a HypoKit with a disposable prefilled syringe containing 1 ml Sterile Water for Reconstitution. Glucagon, as supplied at pH 2.5-3.5, is soluble in water.

Active Ingredient in each vial

Glucagon as hydrochloride 1 mg (corresponding to 1 unit).

Other Ingredients

Lactose monohydrate (107 mg)

When the glucagon powder is reconstituted with Sterile Water for Reconstitution (if supplied) or with Sterile Water for Injection, USP, it forms a solution of 1 mg (1 unit)/ml glucagon for subcutaneous (sc), intramuscular (im), or intravenous (iv) injection.

GlucaGen^® is an antihypoglycemic agent, and a gastrointestinal motility inhibitor.

Clinical Pharmacology

Intramuscular (im) injection of GlucaGen^® resulted in a mean C_max (CV%) of 1686 pg/ml (43%) and median T_max of 12.5 minutes. The mean apparent half-life of 45 minutes after im injection probably reflects prolonged absorption from the injection site. Glucagon is degraded in the liver, kidney, and plasma.¹

Antihypoglycemic Action:

Glucagon induces liver glycogen breakdown, releasing glucose from the liver. Blood glucose concentration rises within 10 minutes of injection and maximal concentrations are attained at approximately a half hour after injection (see Figure). Hepatic stores of glycogen are necessary for glucagon to produce an antihypoglycemic effect.

Recovery from insulin induced hypoglycemia (mean blood glucose) after im injection of 1 mg GlucaGen^® in Type I diabetic men

Glugagen Gastrointestinal Motility Inhibition

Gastrointestinal Motility Inhibition: Extra hepatic effects of glucagon include relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon.

Indications and Usage

For the treatment of hypoglycemia:

GlucaGen^® is used to treat severe hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes treated with insulin. Because GlucaGen^® depletes glycogen stores, the patient should be given supplemental carbohydrates as soon as he/she awakens and is able to swallow, especially children or adolescents. Medical evaluation is recommended for all patients who experience severe hypoglycemia.

For use as a diagnostic aid:

GlucaGen^® is indicated for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. Glucagon is as effective for this examination as are the anticholinergic drugs. However, the addition of the anticholinergic agent may result in increased side effects. Because GlucaGen^® depletes glycogen stores, the patient should be given oral carbohydrates as soon as the procedure is completed.

Contraindications

Glucagon is contraindicated in patients with known hypersensitivity to glucagon or any constituent in GlucaGen^® and in patients with pheochromocytoma or with insulinoma.

Warnings

GlucaGen^® should be administered cautiously to patients suspected of having pheochromocytoma or insulinoma. Secondary hypoglycemia may occur and should be countered by adequate carbohydrate intake following glucagon treatment.

Glucagon may release catecholamines from pheochromocytomas and is contraindicated in patients with this condition.

Allergic reactions may occur and include generalized rash, and in rare cases anaphylactic shock with breathing difficulties, and hypotension. The anaphylactic reactions have generally occurred in association with endoscopic examination during which patients often received other agents including contrast media and local anesthetics. The patients should be given standard treatment for anaphylaxis including an injection of epinephrine if they encounter respiratory difficulties after GlucaGen^® injection.

Precautions

General

In order for GlucaGen^® treatment to reverse hypoglycemia, adequate amounts of glucose must be stored in the liver (as glycogen). Therefore, GlucaGen^® should be used with caution in patients with conditions such as prolonged fasting, starvation, adrenal insufficiency or chronic hypoglycemia because these conditions result in low levels of releasable glucose in the liver and an inadequate reversal of hypoglycemia by GlucaGen^® treatment. Caution should be observed when glucagon is used in diabetic patients or in elderly patients with known cardiac disease to inhibit gastrointestinal motility.

Information for Patients

Refer patients and family members to the "INFORMATION FOR PATIENTS" for instructions describing the method of preparing and injecting GlucaGen^®. Advise the patient and family members to become familiar with the technique of preparing glucagon before an emergency arises. Instruct patients to use 1 mg for adults or ½ the adult dose (0.5 mg) for children weighing less than 55 lbs (25 kg). To prevent severe hypoglycemia, patients and family members should be informed of the symptoms of mild hypoglycemia and how to treat it appropriately. Family members should be informed to arouse the patient as quickly as possible because prolonged hypoglycemia may result in damage to the central nervous system. Patients should be advised to inform their physician when hypoglycemic reactions occur so that the treatment regimen may be adjusted if necessary.

Laboratory Tests

Blood glucose measurements may be considered to monitor the patient's response.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to evaluate carcinogenic potential have not been performed. Several studies have been conducted to evaluate the mutagenic potential of glucagon. The mutagenic potential tested in the Ames and human lymphocyte assays, was borderline positive under certain conditions for both glucagon (pancreatic) and glucagon (rDNA) origin. In vivo, very high doses (100 and 200 mg/kg) of glucagon (both origins) gave a slightly higher incidence of micronucleus formation in male mice but there was no effect in females. The weight of evidence indicates that GlucaGen^® is not different from glucagon pancreatic origin and does not pose a genotoxic risk to humans.

GlucaGen^® was not tested in animal fertility studies. Studies in rats have shown that pancreatic glucagon does not cause impaired fertility.

Pregnancy - Pregnancy Category B

Reproduction studies were performed in rats and rabbits at GlucaGen^® doses of 0.4, 2.0, and 10 mg/kg. These doses represent exposures of up to 100 and 200 times the human dose based on mg/m2 for rats and rabbits, respectively, and revealed no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GlucaGen^® is administered to a nursing woman.

No clinical studies have been performed in nursing mothers, however, GlucaGen® is a peptide and intact glucagon is not absorbed from the GI tract. Therefore, even if the infant ingested glucagon it would be unlikely to have any effect on the infant. Additionally, GlucaGen® has a short plasma half-life thus limiting amounts available to the child.

Pediatric use

For the treatment of hypoglycemia: The use of glucagon in pediatric patients has been reported to be safe and effective.

For use as a diagnostic aid: Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

Severe side effects are very rare, although nausea and vomiting may occur occasionally especially with doses above 1 mg or with rapid injection (less than 1 minute).1 Hypotension has been reported up to 2 hours after administration in patients receiving GlucaGen^® as premedication for upper GI endoscopy procedures. Glucagon exerts positive inotropic and chronotropic effect and may, therefore, cause tachycardia and hypertension. Adverse reactions indicating toxicity of GlucaGen^® have not been reported. A transient increase in both blood pressure and pulse rate may occur following the administration of glucagon. Patients taking ÃŸ-blockers might be expected to have a greater increase in both pulse and blood pressure, an increase of which will be transient because of glucagon's short half-life. The increase in blood pressure and pulse rate may require therapy in patients with pheochromocytoma or coronary artery disease. (see OVERDOSAGE).

Allergic reactions may occur in rare cases. (see WARNINGS).

Overdose

Signs and Symptoms

No reports of overdosage with GlucaGen^® have been reported. It is expected, if overdosage occurred, that the patient may experience nausea, vomiting, inhibition of GI tract motility, increase in blood pressure and pulse rate.1 In case of suspected overdosing, the serum potassium may decrease and should be monitored and corrected if needed.

The IV and SC LD₅₀ for GlucaGen^® in rats and mice ranges from 100 to greater than 200 mg/kg body weight.

Treatment

Standard symptomatic treatment may be undertaken if overdosage occurs. If the patient develops a dramatic increase in blood pressure, 5 to 10 mg of phentolamine mesylate has been shown to be effective in lowering blood pressure for the short time that control would be needed. It is unknown whether GlucaGen^® is dialyzable, but such a procedure is unlikely to provide any benefit given the short half-life and nature of the symptoms of overdose.

Dosage and Administration

Directions for treatment of severe hypoglycemia:

Using the supplied prefilled syringe, carefully insert the needle through the rubber stopper of the vial containing GlucaGen^® powder and inject all the liquid from the syringe into the vial. Roll the vial gently until powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency. The reconstituted GlucaGen^® gives a concentration of approximately 1 mg/ml glucagon. The reconstituted GlucaGen^® should be used immediately after reconstitution. Discard any unused portion. Inject 1 ml (adults and children, weighing more than 55 lbs) or ½ ml (children weighing less than 55 lbs) subcutaneously (s.c), intramuscularly (i.m), or intravenously (i.v). If the weight is not known: Children younger than 6 to 8 years should be given half dose (= ½ ml) and children older than 6 to 8 should be given the adult dose (1ml). Emergency assistance should be sought if the patient fails to respond within 15 minutes after subcutaneous or intramuscular injection of glucagon. The glucagon injection may be repeated while waiting for emergency assistance.1 Intravenous glucose MUST be administered if the patient fails to respond to glucagon. When the patient has responded to the treatment, give oral carbohydrate to restore the liver glycogen and prevent recurrence of hypoglycemia.

Directions for use as a diagnostic aid:

GlucaGen^® should be reconstituted with the supplied 1 ml of Sterile Water for Reconstitution (if supplied) or 1 ml Sterile Water for Injection, USP. Using a syringe, withdraw all of the Sterile Water for Reconstitution (if supplied) or 1 ml Sterile Water for Injection, USP and inject into the GlucaGen® vial. Roll the vial gently until powder is completely dissolved and no particles remain in the fluid. The reconstituted fluid should be clear and of water-like consistency. The reconstituted GlucaGen^® gives a concentration of approximately 1 mg/ml glucagon. The reconstituted GlucaGen^® should be used immediately after reconstitution. Discard any unused portion. When the diagnostic procedure is over, give oral carbohydrate to restore the liver glycogen and prevent occurrence of secondary hypoglycemia.

References for diagnostic aid use only:

Time of maximal glucose concentration

Time for GI smooth muscle relaxation

Intravenous: 5 to 20 minutes

Intravenous: 0.25 to 2 mg (IU) - 45 seconds

Intramuscular: 30 minutes

Subcutaneous: 30 to 45 minutes

Intramuscular:

1 mg (IU) - 8 to 10 minutes

2 mg (IU) - 4 to 7 minutes

Duration of action -

Hyperglycemic action - 60 to 90 minutes

Smooth muscle relaxation -

Intravenous:

0.25 to 0.5 mg (IU) - 9 to 17 minutes

2 mg (IU) - 22 to 25 minutes

Intramuscular:

1 mg (IU) - 12 to 27 minutes

2 mg (IU) - 21 to 32 minutes

Stability and Storage

Before Reconstitution:

The GlucaGen^® package may be stored up to 24 months at controlled room temperature 20^o to 25^o C (68^o to 77^o F) prior to reconstitution. Avoid freezing and protect from light. GlucaGen^® should not be used after the expiry date on the vials.

After Reconstitution:

Reconstituted GlucaGen^® should be used immediately. Discard any unused portion. If the solution shows any sign of gel formation or particles, it should be discarded.

How Supplied

GlucaGen^® HypoKit includes:

1 vial containing 1 mg (1 unit) GlucaGen® (glucagon [rDNA origin] for injection)

1 disposable syringe containing 1 ml Sterile Water for Reconstitution

NDC 0169-7065-15

OR

GlucaGen^® Diagnostic Kit includes:

1 vial containing 1 mg (1 unit) GlucaGen^® (glucagon [rDNA origin] for injection)

1 vial containing 1ml Sterile Water for Reconstitution

NDC 55390-004-01

OR

The GlucaGen^® 10-pack includes:

10x1 vial containing 1 mg (1 unit) GlucaGen® (glucagon [rDNA origin] for injection)

NDC 55390-004-10

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

Information for Patients

GlucaGen^® HypoKit

Emergency Use for Low Blood Sugar

(glucagon [rDNA origin] for injection) 1 mg.

BECOME FAMILIAR WITH THE FOLLOWING INSTRUCTIONS BEFORE AN EMERGENCY ARISES. DO NOT USE THIS PACKAGE AFTER THE EXPIRATION DATE. IF YOU HAVE QUESTIONS CONCERNING THE USE OF THIS PRODUCT, CONSULT A DOCTOR, NURSE, OR PHARMACIST.

Make sure that your relatives or close friends know that if you become unconscious, medical assistance must always be sought. GlucaGen^® may have been prescribed so that members of your household can give the injection if you become hypoglycemic (low blood sugar) and are unable to take sugar by mouth. If you are unconscious, GlucaGen^® can be given while awaiting medical assistance.

Show your family members and others where you keep this kit and how to use it. They need to know how to prepare it before you need it. They can practice giving a shot by giving you your normal insulin shots. It is important that they practice. A person who has never given a shot probably will not be able to do it in an emergency.

IMPORTANT

Act quickly. Prolonged unconsciousness may be harmful.
These simple instructions will help you give glucagon successfully.
Turn patient on his/her side to prevent choking.
The content of the syringe does not contain glucagon. You must mix the contents of the syringe with the glucagon in the accompanying bottle before giving injection. (see DIRECTIONS FOR USE)
Do not mix GlucaGen^® until you are ready to use it.
Discard any unused portion.
Become familiar with the technique of preparing glucagon before an emergency arises.
WARNING: THE PATIENT MAY BE IN A COMA FROM SEVERE HYPERGLYCEMIA (HIGH BLOOD SUGAR) RATHER THAN HYPOGLYCEMIA (LOW BLOOD SUGAR). IN SUCH A CASE, THE PATIENT WILL NOT RESPOND TO GLUCAGON AND REQUIRES IMMEDIATE MEDICAL ATTENTION.

INDICATION FOR USE

GlucaGen^® is used to treat severe hypoglycemic (low blood sugar) reactions which may occasionally occur in patients with diabetes. Symptoms of severe hypoglycemic reactions include disorientation, loss of consciousness, and seizures. You should only give GlucaGen^® injection if (1) the patient is unconscious, (2) the patient is having a seizure, or (3) the patient is disoriented and unable to eat sugar or a sugar-sweetened product. Milder cases of hypoglycemia should be treated promptly by eating sugar or a sugar-sweetened product such as a regular soft drink or fruit juice. GlucaGen^® does not work if it is taken by mouth.

DIRECTIONS FOR USE:

To Prepare GlucaGen^® For Injection:

Use the enclosed prefilled disposable syringe with the attached needle to reconstitute GlucaGen® before giving the injection.

Step 1. Take off the orange plastic cap off the vial. Pull the needle cover off the syringe. Insert the needle through the rubber stopper of the vial containing GlucaGen® and inject all the liquid from the syringe into the vial.

Glucagen Step 1

Step 1

Step 2. Without taking the syringe with a needle out of the vial, gently shake the vial in your hand until the powder has completely dissolved, and the solution is clear.

Glucagen Step 2

Step 2

Step 3. While the needle is still inside the vial, turn the vial upside down and while keeping the needle in the liquid, slowly withdraw all the liquid into the syringe. Be careful not to pull theplunger out of the syringe. This will also help minimize the leakage of the fluid around the syringe. The usual dose for adult and children weighing more than 55 lbs is 1 mg (1 ml). Therefore, withdraw the solution to 1 ml mark on the syringe. The usual dose for children weighing less than 55 lb is 0.5 mg (1/2 adult dose). Therefore, withdraw ½ of the solution from the vial (0.5 ml mark on the syringe) for these children. DISCARD UNUSED PORTION.

Glucagen Step 3

Step 3

To Inject GlucaGen^®

Step 4. Turn the patient on his/her side. When an unconscious person awakens, he/she may vomit. Turning the patient on his/her side will prevent him/her from choking. Without removing the needle from the vial and while keeping the needle in the liquid, remove any air bubble(s) in the syringe by flicking the syringe with your finger and squirting any air bubbles out of the needle into the vial. Continue pushing the plunger until you have the correct dose as described in Step 3. In the event the plunger is pushed below the required dose, pull back the plunger until you have the correct dose. When you have a correct amount of glucagon in the syringe, pull the syringe with a needle from the vial. Insert the needle into the loose tissue under the injection site, and inject the glucagon solution. THERE IS NO DANGER OF OVERDOSE.

Glucagen Step 4

Step 4

After Giving the Injection

Step 5. Withdraw the needle and press on the injection site. Used syringe and needle should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

Step 6. FEED THE PATIENT AS SOON AS HE/SHE AWAKENS AND IS ABLE TO SWALLOW. Give the patient a fast-acting source of sugar (such as a regular soft drink or fruit juice) and a long-acting source of sugar (such as crackers and cheese or a meat sandwich). If the patient does not awaken within 15 minutes, give another dose of GlucaGen^® and INFORM A DOCTOR OR EMERGENCY SERVICES IMMEDIATELY.

Step 7. Even if the GlucaGen^® awakens the patient, his/her doctor should be promptly notified. A doctor should be notified whenever severe hypoglycemic reactions happen.

How GlucaGen^® Works

GlucaGen^® (glucagon [rDNA origin] for injection) is quickly absorbed after injection under the skin or into the muscle. Glucagon action causes glucose (sugar) to be released from the liver where it is stored as glycogen. Blood sugar levels increase within 10 minutes of injection and reach the highest amount approximately half an hour after injection. Glucagon works by promoting the release of glycogen (stored sugar in the liver).

When GlucaGen^®Should Not Be Used

Do not use GlucaGen^® if a patient is allergic to glucagon.

WARNINGS

Hypoglycemia may occur again following glucagon treatment. Tell your friends or relatives that you must be given a fast-acting source of sugar (such as regular soft drink or fruit juice), followed by a long acting source of sugar (carbohydrates) by mouth as soon as you are able to take it after you have responded to treatment - this will prevent the return of hypoglycemia (low blood sugar). Early symptoms of hypoglycemia may include:

perspiration
drowsiness
dizziness
sleep disturbances
palpitation
anxiety
tremor
blurred vision
hunger
slurred speech
restlessness
depressed mood
tingling in the hands, feet, lips, or tongue
irritability
abnormal behavior
lightheadedness
unsteady movement
inability to concentrate
personality changes
headache

Allergic reactions may occur rarely and include generalized rash, anaphylactic shock, breathing difficulties and hypotension (low blood pressure).

Keep this kit out of reach of children.

PRECAUTIONS

General - GlucaGen^® is only of benefit in hypoglycemia (low blood sugar) when the liver has sufficient glucose (in the form of glycogen) to release. For that reason GlucaGen^® has little or no effect if you are fasting, or if you are suffering from adrenal insufficiency, chronic hypoglycemia or alcohol induced hypoglycemia. Remember GlucaGen^® has the opposite effect of insulin.

If the GlucaGen solution shows any sign of gel formation or particles it should be discarded.

Your GlucaGen^® HypoKit for hypoglycemia (low blood sugar) includes:

One vial of 1 mg GlucaGen^® (glucagon [rDNA origin] for injection)
One prefilled disposable syringe with attached needle containing 1 ml Sterile Water for Reconstitution

The vial has a protective plastic cap. You must remove the plastic cap to inject the water and reconstitute the freeze-dried GlucaGen®. If the cap is loose or missing when you buy the package, return it to your local pharmacy.

Pregnancy - GlucaGen^® is glucagon which is a hormone that is always present in humans. GlucaGen® is intended for infrequent use during acute, severe hypoglycemic attacks, and may be used during pregnancy.

Nursing Mothers - Breast feeding following treatment with GlucaGen® for your hypoglycemic attack should not put your baby at risk. GlucaGen® does not stay very long in the body. Also, because glucagon is a protein, even if the infant ingested glucagon, it would be unlikely to have any effect on the infant because it would be digested.

POSSIBLE PROBLEMS WITH GlucaGen^® TREATMENT

Severe side effects are very rare, although nausea and vomiting may occur occasionally. Side effects indicating toxicity of GlucaGen® have not been reported.

A few people may be allergic to glucagon or to one of the inactive ingredients in GlucaGen®, or may experience rapid heart beat for a short while.

If you experience any other reactions which are likely to have been caused by GlucaGen®, please contact your doctor.

EXPIRATION DATE

Before mixing - The GlucaGen® package may be stored up to 24 months at controlled room temperature 20o to 25o C (68o to 77o F) prior to reconstitution. Avoid freezing and protect from light. Never use GlucaGen® after the expiration date printed on the package. GlucaGen^® does not contain preservatives and is for single use only.

After mixing - Reconstituted GlucaGen® should be used immediately. Discard any unused portion.

GlucaGen^® is a registered trademark of Novo Nordisk A/S

© Novo Nordisk A/S, 2005

For information contact:

Novo Nordisk Inc.

Princeton, New Jersey 08540

1-800-727-6500

www.novonordisk-us.com

Manufactured by:

Novo Nordisk^® A/S

2880 Bagsvaerd, Denmark

Last Updated: 11/05

GlucaGen, glucagon hydrochloride, patient information (in plain English)