Novolog 70/30

NOVOLOG MIX 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus.

• •NOVOLOG MIX 70/30 is not recommended for the treatment of diabetic ketoacidosis.
• •The proportions of rapid-acting and long-acting insulins in NOVOLOG MIX 70/30 are fixed and do not allow for basal versus prandial dose adjustments.

• •Inspect visually before use. Appearance should be uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles (
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
  ).
• •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature (
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
  ).
• •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
• •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation (
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
  ).
• •Rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
  .
• •Do
  not
  administer intravenously or use in insulin infusion pumps (
  2.1 Important Preparation and Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • •Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
  • •NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
  • •When using the:
  • oVial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • oNOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
  • •The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
  • •Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • •Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
  • •Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
  • •Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis
    [see Warnings and Precautions (5.2)and Adverse Reactions].
  • •Do
    not
    administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
  • •Do
    not
    mix NOVOLOG MIX 70/30 with any other insulins.
  ).
• •NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack)
  2.2 Dosage Recommendations

  • •NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
  • •Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
  • •Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness
    [see Warnings and Precautions and Use in Specific Populations ]
    .
  • •When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed
    [see Warnings and Precautions (5.2)]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  .
• •Individualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal (
  2.2 Dosage Recommendations

  • •NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
  • •Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
  • •Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness
    [see Warnings and Precautions and Use in Specific Populations ]
    .
  • •When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed
    [see Warnings and Precautions (5.2)]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  ).
• •Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness (
  2.2 Dosage Recommendations

  • •NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
  • •Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
  • •Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness
    [see Warnings and Precautions and Use in Specific Populations ]
    .
  • •When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed
    [see Warnings and Precautions (5.2)]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  ).
• •When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed (
  2.2 Dosage Recommendations

  • •NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
  • •Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
  • •Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness
    [see Warnings and Precautions and Use in Specific Populations ]
    .
  • •When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed
    [see Warnings and Precautions (5.2)]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  ).

Injectable suspension: 100 units/mL (U-100) of NOVOLOG MIX 70/30, 70% insulin aspart protamine and 30% insulin aspart, is a white and cloudy suspension available as:

• •10 mL multiple-dose vial
• •3 mL single-patient-use FlexPen prefilled pen

There are no available data with NOVOLOG MIX 70/30 in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes

In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of 1 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA_1c >7% and has been reported to be as high as 20-25% in women with a HbA_1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart during the late 2^nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials.

Fertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

• •Never share a NOVOLOG MIX 70/30 FlexPen between patients, even if the needle is changed
  5.1 Never Share NOVOLOG MIX 70/30 FlexPen Between Patients

  NOVOLOG MIX 70/30 FlexPen should never be shared between patients, even if the needle is changed. Patients using NOVOLOG MIX 70/30 vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
  .
• •
  Hyperglycemia or hypoglycemia with changes in insulin regimen:
  Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring
  5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

  Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia

  [ see Warnings and Precautions (5.3)]

  or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia

  [ see Adverse Reactions(

  6.1

  , 6.3)]

  . Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.
  .
• •
  Hypoglycemia:
  May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitantly administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness
  5.3 Hypoglycemia

  Hypoglycemia is the most common adverse reaction of all insulins, including NOVOLOG MIX 70/30. Severe hypoglycemia can cause seizures, may lead to unconsciousness, 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.g., driving or operating other machinery).

  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.g., beta-blockers)

  [see Drug Interactions (7)]

  , or in patients who experience recurrent hypoglycemia.

  Risk Factors for Hypoglycemia

  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 insulins, the glucose lowering effect time course of NOVOLOG MIX 70/30 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 (12.2)]

  . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitantly administered medication

  [see Drug Interactions (7)]

  . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia

  [see Use in Specific Populations (8.6, 8.7)].

  Risk Mitigation Strategies for Hypoglycemia

  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; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
  .
• •
  Medication Errors:
  Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection
  5.4 Hypoglycemia Due to Medication Errors

  Accidental mix-ups between insulin products have been reported. To avoid medication errors between NOVOLOG MIX 70/30 and other insulins, instruct patients to always check the insulin label before each injection.
  .
• •
  Hypersensitivity reactions:
  Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue NOVOLOG MIX 70/30, treat, and monitor, if indicated
  5.5 Hypersensitivity Reactions

  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including NOVOLOG MIX 70/30. If hypersensitivity reactions occur, discontinue NOVOLOG MIX 70/30; treat per standard of care and monitor until symptoms and signs resolve

  [see Adverse Reactions (6)].

  NOVOLOG MIX 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients

  [see Contraindications (4)].
  .
• •
  Hypokalemia:
  May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated
  5.6 Hypokalemia

  All insulins, including NOVOLOG MIX 70/30, can 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.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentration).
  .
• •
  Fluid retention and heart failure with
  concomitant use of
  thiazolidinediones (TZDs)
  : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs
  5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

  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 NOVOLOG MIX 70/30, 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.
  .