However, this rule failed to motivate many drug companies to conduct additional pediatric drug trials. Similar effects were observed with NPH insulin. It has an extremely tart, acidic taste, which is useful in some foods. Whether non-nutritive sweeteners are safe depends on your definition of safe. One-sixth as sweet as sugar, it is used as a slightly sweet source of carbohydrate.
Products manufactured or imported into Canada that contain non-permitted ingredients vegetable fats or oils, artificial sweeteners cannot legally be called "chocolate" when sold in Canada. A non-standardized name such as "candy" must be used. In Japan, 'chocolate products' are classified on a complex scale q. Chocolate is a product based on cocoa solid or cocoa fat or both. The amount and types of cocoa solids and fat that the term implies is a matter of controversy.
Manufacturers have an incentive to use the term for variations that are cheaper to produce, containing less cocoa and more cocoa substitutes.
There has been disagreement in the EU about the definition of chocolate; this dispute covers several ingredients, including the types of fat used and the quantity of cocoa. A recent workaround has been to reduce the amount of cocoa butter in candy bars without using vegetable fats by adding polyglycerol polyricinoleate PGPR , which is an artificial castor oil-derived emulsifier that simulates the mouthfeel of fat.
Cacao beans can be tested for their quality as a certain variety using DNA tests, especially by testing single-nucleotide polymorphisms that act as markers. From Wikipedia, the free encyclopedia. Candy making Chocolate bar List of bean-to-bar chocolate manufacturers List of desserts. Archived from the original on 2 January Retrieved 5 December The New York Times.
Archived from the original on 14 May Retrieved 1 January Archived from the original on 5 December Archived from the original on 11 June Retrieved 30 May The Art and Soul of Baking. Archived from the original on 23 March Retrieved 3 March Archived from the original on 11 November Title 21 — Food and Drugs.
Archived from the original on 10 March Retrieved 1 May Archived from the original on 26 January Archived from the original PDF on 2 December Retrieved 27 January Canadian Food Inspection Agency Act. Department of Justice Canada. Archived from the original on 6 April Retrieved 16 February Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions 5.
These changes should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.
Hypoglycemia is the most common adverse reaction associated with insulins, including Basaglar [see Adverse Reactions 6. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important e. Basaglar, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications 4 ].
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system e.
The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of Basaglar may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology The risk of hypoglycemia generally increases with intensity of glycemic control.
Other factors which may increase the risk of hypoglycemia include changes in meal pattern e. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations 8.
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia.
In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To avoid medication errors between Basaglar and other insulins, instruct patients to always check the insulin label before each injection.
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Basaglar. If hypersensitivity reactions occur, discontinue Basaglar; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions 6.
Basaglar is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients [see Contraindications 4 ]. All insulin products, including Basaglar, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated e.
Thiazolidinediones TZDs , which are peroxisome proliferator-activated receptor PPAR -gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Basaglar, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure.
If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Two clinical trials with Basaglar were conducted: The type 1 diabetes population had the following characteristics: Mean age was 41 years and mean duration of diabetes was 16 years.
HbA 1c at baseline was 7. The data in Table 1 reflect exposure of patients to Basaglar with a mean exposure duration of 49 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 11 years. HbA 1c at baseline was 8. The data in Table 2 reflect exposure of patients to Basaglar with a mean exposure duration of 22 weeks. Common adverse reactions during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus other than hypoglycemia are listed in Table 1 and Table 2 , respectively.
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Basaglar [see Warnings and Precautions 5. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors.
For these reasons, comparing rates of hypoglycemia in clinical trials for Basaglar with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. Some patients taking insulin therapy, including Basaglar have experienced erythema, local edema, and pruritus at the site of injection.
These conditions were usually self-limiting. Severe cases of generalized allergy anaphylaxis have been reported [see Warnings and Precautions 5. Some patients taking Basaglar have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
Administration of insulin subcutaneously, including Basaglar, has resulted in lipoatrophy depression in the skin or lipohypertrophy enlargement or thickening of tissue in some patients [see Dosage and Administration 2.
Weight gain has occurred with some insulin therapies including Basaglar and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. The percent binding of patients positive at baseline on Basaglar did not increase significantly during the study. There was no evidence that these antibodies had an impact on efficacy and safety outcomes.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: For these reasons, comparison of the incidence of antibodies to Basaglar with the incidence of antibodies in other studies or to other products may be misleading.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.
Medication errors have been reported in which other insulin products, particularly rapid-acting insulins, have been accidentally administered instead of an insulin glargine product.
To avoid medication errors between insulin glargine products and other insulin products, patients should be instructed to always verify the insulin label before each injection. Table 6 includes clinically significant drug interactions with Basaglar.
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy.
In patients with diabetes or gestational diabetes, 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 these patients.
Therefore, female patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking Basaglar. There are no well-controlled clinical studies of the use of insulin glargine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Subcutaneous reproduction and teratology studies have been performed with another insulin glargine product and with regular human insulin in rats and Himalayan rabbits.
This other insulin glargine product was given to female rats before mating, during mating, and throughout pregnancy at dose up to 0. In rabbits, doses of 0. The effects of this other insulin glargine product did not generally differ from those observed with regular human insulin in rats and 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.
Endogenous insulin is present in human milk; it is unknown whether insulin glargine is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when Basaglar is administered to a nursing woman. Use of Basaglar is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.
The safety and effectiveness of Basaglar in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes has not been established.
The dosage recommendation when changing to Basaglar in pediatric patients age 6 to 15 years with type 1 diabetes is the same as that described for adults [see Dosage and Administration 2. As in adults, the dosage of Basaglar must be individualized in pediatric patients age 6 to 15 years with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose. In the pediatric clinical trial, pediatric patients age 6 to 15 years with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see Adverse Reactions 6.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Nevertheless, caution should be exercised when Basaglar is administered to geriatric 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. The effect of renal impairment on the pharmacokinetics of Basaglar has not been studied.
Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and dose adjustment may be necessary for Basaglar in patients with renal impairment [see Warnings and Precautions 5. The effect of hepatic impairment on the pharmacokinetics of Basaglar has not been studied.
However, as with all insulin products, more frequent glucose monitoring and dose adjustment may be necessary for Basaglar in patients with hepatic impairment [see Warnings and Precautions 5. Excess insulin administration relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions 5. Mild episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level may be needed.
Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately. Basaglar insulin glargine injection is a long-acting insulin for subcutaneous use.
Insulin glargine is a recombinant human insulin analog [see Clinical Pharmacology 12 ]. Basaglar 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. Insulin glargine has the following structural formula:. Basaglar is a clear, colorless, sterile aqueous solution of insulin glargine.
The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. Basaglar has a pH of approximately 4. The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analog lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.
The pharmacodynamic profile for Basaglar was determined after subcutaneous administration of a single 0. The median time to maximum effect of Basaglar measured by the peak rate of glucose infusion was approximately The pharmacodynamic profile of Basaglar following subcutaneous injection demonstrated sustained glucose lowering activity over 24 hours with no pronounced peak.
A euglycemic clamp study in 20 patients with type 1 diabetes showed a similar pharmacodynamic profile with a sustained glucose lowering activity over 24 hours following a single 0.
After subcutaneous injection of 0. The time course of action of insulins, including insulin glargine, may vary between individuals and within the same individual. The pharmacokinetic profile for Basaglar was determined after subcutaneous administration of a single 0.
The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The in vitro activity of M1 and M2 were similar to that of insulin. Age, Race, and Gender: Effect of age, race, and gender on the pharmacokinetics of Basaglar has not been evaluated.
Effect of BMI on the pharmacokinetics of Basaglar has not been evaluated. In mice and rats, standard two-year carcinogenicity studies with another insulin glargine product were performed at doses up to 0. 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. Another insulin glargine product 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 of another insulin glargine product in male and female rats at subcutaneous doses up to 0. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin. In general, the reduction in glycated hemoglobin HbA 1c with this other insulin glargine product was similar to that with NPH insulin.
Randomized were adults with type 1 diabetes. Mean age was The mean BMI was approximately Observed HbA 1c data at 24 weeks were available from Regular human insulin was administered before each meal. This other insulin glargine product was administered at bedtime. NPH insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily.
In Study A, the average age was The mean duration of diabetes was In Study B, the average age was The majority of patients were Caucasian Insulin lispro was used before each meal.
This other insulin glargine product was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was Type 1 Diabetes — Pediatric see Table 9. Patients were randomized to either this other insulin glargine product administered once daily at bedtime or NPH insulin administered once or twice daily. The mean duration of diabetes was 4.
Similar effects on HbA 1c see Table 9 were observed in both treatment groups. A total of patients were randomized. Three patients randomized to Basaglar did not receive study drug and were not included in efficacy analysis. The average age was approximately 59 years.
This other insulin glargine product administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA 1c and fasting glucose see Table The rate of hypoglycemia was similar in this other insulin glargine product and NPH insulin treated patients [see Adverse Reactions 6.
Regular human insulin was used before meals, as needed. This other insulin glargine product had similar effectiveness as either once- or twice daily NPH insulin in reducing HbA 1c and fasting glucose see Table 11 with a similar incidence of hypoglycemia [see Adverse Reactions 6.
The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the ETDRS scale. HbA 1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. After this other insulin glargine product or NPH insulin dose was adjusted, other anti-diabetic agents, including pre-meal insulin were to be adjusted or added.
This other insulin glargine product group had a smaller mean reduction from baseline in HbA 1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in this other insulin glargine product group see Table Both treatment groups had a similar incidence of reported symptomatic hypoglycemia. Patients were also treated with insulin lispro at mealtime. This other insulin glargine product administered at different times of the day resulted in similar reductions in HbA 1c compared to that with bedtime administration see Table In these patients, data are available from 8-point home glucose monitoring.
The maximum mean blood glucose was observed just prior to injection of this other insulin glargine product regardless of time of administration. No patients in the other two arms discontinued for this reason. This other insulin glargine product given before breakfast was at least as effective in lowering HbA 1c as this other insulin glargine product given at bedtime or NPH insulin given at bedtime see Table Five-year Trial Evaluating the Progression of Retinopathy.
The numbers of retinal adverse events reported for this other insulin glargine product and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes. Mean baseline HbA 1c was 8.
Patients with pre-specified post-baseline eye procedures pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy were also considered as 3-step progressions regardless of actual change in ETDRS score from baseline.
Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of this other insulin glargine product to NPH in the progression of diabetic retinopathy as assessed by this outcome. The objective of the trial was to demonstrate that use of this other insulin glargine product could significantly lower the risk of major cardiovascular outcomes compared to standard care.
The first co-primary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. The second co-primary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.
Anthropometric and disease characteristics were balanced at baseline. The mean HbA 1c SD at baseline was 6. Vital status was available for The median duration of follow-up was 6. The mean HbA 1c SD at the end of the trial was 6. The median dose of this other insulin glargine product at end of trial was 0.