LANTUS — insulin glargine injection, solution
Physicians Total Care, Inc.
LANTUS is indicated to improve glycemic control in adults and children with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.
Important Limitations of Use:
- LANTUS is not recommended for the treatment of diabetic ketoacidosis. Intravenous short-acting insulin is the preferred treatment for this condition.
LANTUS is a recombinant human insulin analog for once daily subcutaneous administration with potency that is approximately the same as the potency of human insulin. LANTUS 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. The dose of LANTUS must be individualized based on clinical response. Blood glucose monitoring is essential in all patients receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LANTUS, should only do so under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1).]
In patients with type 1 diabetes, LANTUS must be used in regimens with short-acting insulin.
The intended duration of activity of LANTUS is dependent on injection into subcutaneous tissue [see Clinical pharmacology (12.2)]. LANTUS should not be administered intravenously or via an insulin pump. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.3)].
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid) from one injection to the next to reduce the risk of lipodystrophy [See Adverse Reactions (6.1)].
In clinical studies, there was no clinically 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, such as stress, intercurrent illness, or changes in co-administered drugs or meal patterns.
The recommended starting dose of LANTUS in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LANTUS in patients with type 2 diabetes who are not currently treated with insulin is 10 units (or 0.2 Units/kg) once daily, which should subsequently be adjusted to the patient’s needs.
The dose of LANTUS should be adjusted according to blood glucose measurements. The dosage of LANTUS should be individualized under the supervision of a healthcare provider in accordance with the needs of the patient.
If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with LANTUS, the amount and timing of shorter-acting insulins and doses of any oral anti-diabetic drugs may need to be adjusted.
- If transferring patients from once-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is the same as the dose of NPH that is being discontinued.
- If transferring patients from twice-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is 80% of the total NPH dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)].
LANTUS solution for injection 100 Units per mL is available as:® (300 Units/3 mL)-3 mL SoloStar® disposable insulin device (300 Units/3 mL)
LANTUS is contraindicated in patients with hypersensitivity to LANTUS or one of its excipients.
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose or an adjustment in concomitant oral anti-diabetic treatment.
As with all insulin preparations, the time course of action for LANTUS may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.
Do not administer LANTUS intravenously or via an insulin pump. The intended duration of activity of LANTUS is dependent on injection into subcutaneous tissue
Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.3)].
Do not dilute or mix LANTUS with any other insulin or solution. If LANTUS is diluted or mixed, the solution may become cloudy, and the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LANTUS and 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 a delayed 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 unknown.
Do not share disposable or reusable insulin devices or needles between patients, because doing so carries a risk for transmission of blood-borne pathogens.
Hypoglycemia is the most common adverse reaction of insulin, including LANTUS. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with LANTUS.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia [See Drug Interactions (7) ].
The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia. 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 (2.3)].
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LANTUS.
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining renal function because of the risk for prolonged hypoglycemia.
Although studies have not been performed in patients with diabetes and renal impairment, a reduction in the LANTUS dose may be required in patients with renal impairment because of reduced insulin metabolism, similar to observations found with other insulins. [See Clinical Pharmacology (12.3)].
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining hepatic function because of the risk for prolonged hypoglycemia.
Although studies have not been performed in patients with diabetes and hepatic impairment, a reduction in the LANTUS dose may be required in patients with hepatic impairment because of reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins. [See Clinical Pharmacology (12.3)].
Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia [See Drug Interactions (7)].
The following adverse reactions are discussed elsewhere:
- Hypoglycemia [See Warnings and Precautions (5.3)]
- Hypersensitivity and allergic reactions [See Warnings and Precautions (5.4)]
Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
The frequencies of treatment-emergent adverse events during LANTUS clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
|LANTUS, %(n=1257)||NPH, %(n=1070)|
|Upper respiratory tract infection||22.4||23.1|
* Body System not Specified
|Upper respiratory tract infection||11.4||13.3|
|Retinal vascular disorder||5.8||7.4|
* Body System not Specified
|LANTUS, %(n=514)||NPH, %(n=503)|
|Upper respiratory tract infection||29.0||33.6|
|Pain in extremity||13.0||13.1|
|Urinary tract infection||10.7||10.1|
|LANTUS, %(nj=174)||NPH, %(n=175)|
|Upper respiratory tract infection||13.8||16.0|
* Body System not Specified
- Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LANTUS [See Warnings and Precautions (5.3)]. Tables 5 and 6 summarize the incidence of severe hypoglycemia in the LANTUS individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤56 mg/dL in the 5-year trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.
The rates of severe symptomatic hypoglycemia in the LANTUS clinical trials (see Section 14 for a description of the study designs) were comparable for all treatment regimens (see Tables 5 and 6). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes. (see Table 5) [See Clinical Studies (14)].
|Study ADiabetes AdultsIn combination||Type 128 weekswith regularinsulin||Study B Diabetes Adults In combination||Type 1 28 weeks with regular insulin||Study C Diabetes Adults In combination||Type 1 16 weeks with insulinlispro||Study D Diabetes Adults In combination||Type 1 26 weeks with regular insulin|
|Percent of patients(n/total N)||10.6(31/292)||15.0(44/293)||8.7(23/264)||10.4(28/270)||6.5(20/310)||5.2(16/309)||23.0(40/174)||28.6(50/175)|
|Study EDiabetes AdultsIn combination with||Type 252 weeksoral agents||Study FDiabetes AdultsIn combination with||Type 228 weeksregular insulin||Study GDiabetes AdultsIn combination with||Type 25 yearsregular insulin|
|Percent of patients(n/totalN)||1.7(5/289)||1.1(3/281)||0.4(1/259)||2.3(6/259)||7.8(40/513)||11.9(60/504)|
Retinopathy was evaluated in the LANTUS clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for LANTUS and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.
LANTUS was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 yrs) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. 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 progressors 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 7 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of Lantus to NPH in the progression of diabetic retinopathy as assessed by this outcome.
|Lantus (%)||NPH (%)||Difference *, † (SE)||95% CI for difference|
|Per-protocol||53/374 (14.2%)||57/363 (15.7%)||-2.0% (2.6%)||-7.0% to +3.1%|
|Intent-to-Treat||63/502 (12.5)||71/487 (14.6%)||-2.1% (2.1%)||-6.3% to +2.1%|
† using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function
- Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.
Long-term use of insulin, including LANTUS, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration (2.1)].
- Weight gain
Weight gain can occur with insulin therapy, including LANTUS, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
- Peripheral Edema
Insulin, including LANTUS, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
- Allergic Reactions
As with any insulin therapy, patients taking LANTUS may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. 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 did not result in discontinuation of therapy.
Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks.
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LANTUS and may be life threatening.
- Antibody production
All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LANTUS, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences.
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