Insulin Glargine (Lantus) Complete Drug-Drug Interaction Profile

How the Semglee and Rezvoglar labels group insulin glargine interactions

Insulin glargine is a long-acting human insulin analog injected once daily under the skin [1]. Part of each dose is broken down in the injection-site depot into two active metabolites, M1 and M2, both structurally similar to human insulin [5]. Lantus is the reference insulin glargine product (BLA 021081, approved April 20, 2000), and Semglee and Rezvoglar are FDA-approved biosimilars of it [3][4].

The Semglee and Rezvoglar prescribing information groups interactions by their effect on blood glucose and on hypoglycemia symptoms, and also warns about thiazolidinediones used with insulin [1][2].

Drugs that may increase the risk of hypoglycemia

The Semglee and Rezvoglar labels list antidiabetic agents, ACE inhibitors, angiotensin II receptor blockers, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs such as octreotide, sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors. For this whole group, the labels say dosage reductions and increased frequency of glucose monitoring may be required when insulin glargine is coadministered [1].

ACE inhibitors. A case-control study nested in a Tayside, Scotland cohort of 6,649 people treated with insulin or oral antidiabetic drugs compared 64 people admitted to hospital with hypoglycemia against 440 controls. ACE inhibitor use was associated with hospital admission for hypoglycemia (odds ratio 3.2, 95% CI 1.2 to 8.3; adjusted odds ratio 4.3, 95% CI 1.2 to 16.0) [6]. That study covered insulin and oral antidiabetic users generally, not insulin glargine specifically.

Drugs that may decrease insulin glargine's effect

A second group on the same labels includes atypical antipsychotics such as olanzapine and clozapine, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens, protease inhibitors, somatropin, sympathomimetic agents such as albuterol, epinephrine and terbutaline, and thyroid hormones. For these, the labels say dosage increases and increased frequency of glucose monitoring may be required [1].

Protease inhibitors. Indinavir 800 mg twice daily for four weeks, given to 10 healthy HIV-negative men, raised fasting glucose from 4.9 to 5.2 mmol/L and reduced insulin-mediated glucose disposal, with no significant change in visceral or subcutaneous fat on CT [7]. It is a small study, and it measured indinavir's own metabolic effect rather than a change in an insulin glargine dose.

Olanzapine. In CATIE, which randomized 1,493 people with chronic schizophrenia, olanzapine was associated with more discontinuation for weight gain or metabolic effects and with greater weight gain [8]. The labels group olanzapine and clozapine among drugs that can reduce insulin glargine's glucose-lowering effect [1].

Corticosteroids. These are on the decrease-effect list, and the labels give no expected size for the dose increase [1].

Alcohol, beta-blockers, clonidine and lithium

Alcohol, beta-blockers, clonidine and lithium salts sit in a third group. They may raise or lower the glucose-lowering effect of insulin glargine, so the labels say dosage adjustment and increased glucose monitoring may be required [1]. Pentamidine is in the same group: it may cause hypoglycemia that is sometimes followed by hyperglycemia [1].

Beta-blockers also appear in a fourth group, as drugs that can blunt the signs and symptoms of hypoglycemia [1]. The Semglee label's hypoglycemia warning makes the same point: symptomatic awareness may be less pronounced in people using drugs that block the sympathetic nervous system, such as beta-blockers, and the long-acting effect of insulin glargine may delay recovery from a low [1]. Clonidine, guanethidine and reserpine are listed alongside beta-blockers, with signs and symptoms of hypoglycemia possibly reduced or absent [1].

The same Tayside study found no association between beta-blocker use and hospital admission for hypoglycemia (odds ratio 0.9, 95% CI 0.3 to 3.3). It measured admissions, not whether people noticed their own symptoms [6].

Pioglitazone and heart failure

Thiazolidinediones are the one interaction on the labels that is not purely about glucose. The Semglee and Rezvoglar labeling warns that pioglitazone and other PPAR-gamma agonists can cause dose-related fluid retention when used with insulin. It says the retention may lead to or worsen heart failure, that people on both should be observed for signs of heart failure, and that dose reduction or discontinuation of the thiazolidinedione should be considered if heart failure develops [1][2].

In PROactive, 5,238 people with type 2 diabetes and macrovascular disease were randomized to pioglitazone or placebo alongside their existing glucose-lowering drugs. Hospital admission for heart failure occurred in 6% of the pioglitazone group and 4% of the placebo group. This trial was not a test of insulin combined with pioglitazone [9]. The Semglee and Rezvoglar labels carry no boxed warning; the thiazolidinedione warning is section 5.7 of the warnings and precautions [1][2].

Monitoring and handling in the labels

The Semglee label's hypoglycemia section says to increase the frequency of glucose monitoring with changes to insulin dosage, concomitant drugs, meal pattern and physical activity, and in people with kidney or liver impairment or reduced hypoglycemia awareness [1]. For type 2 diabetes, the label adds that dosage adjustments of concomitant oral and other antidiabetic products may be needed [1].

One instruction is about handling rather than glucose: the Semglee label says it must not be diluted or mixed with any other insulin or solution [1].

What the labels do not quantify

The Semglee and Rezvoglar labels name the drugs, the expected direction of change and the monitoring they want. They give no percentages or unit amounts for adjusting the insulin glargine dose when an interacting drug is started or stopped [1][2].