Insulin Lispro Protamine + Insulin Lispro

Approved indications

• Diabetes mellitus requiring insulin to improve glycemic control:
• Type 1 diabetes (adult and adolescent): as part of an insulin regimen when a premixed preparation is appropriate (e.g., patients able to take consistent meals).
• Type 2 diabetes (adult): when diet/exercise ± oral agents are insufficient; may be initial insulin (basal-bolus alternative) or used to intensify therapy.

Limitations of use / clinical notes

• Not indicated for the treatment of diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state—use IV regular insulin with appropriate monitoring.
• Not for continuous subcutaneous insulin infusion (CSII/pump) and not for IV administration.
• Use is generally reserved for patients with predictable meal timing; those needing flexible prandial dosing may benefit more from separate rapid-acting plus basal insulin.

Clinically accepted off-label contexts

• Transition therapy from basal insulin alone to premix BID or TID when post-prandial excursions predominate and adherence to multiple injections is a barrier.
• Use in gestational diabetes when insulin is required and rapid-acting coverage around meals is needed (local practice varies; individualized specialist oversight required).

Formulations

• Premixed suspensions containing insulin lispro protamine (intermediate-acting) + insulin lispro (rapid-acting) in fixed ratios (e.g., 75/25 or 50/50). Units are insulin units (U); U-100 strength unless specified.

Route

• Subcutaneous (SC) only. Do not give IV, IM, or via insulin pump.

Timing vs meals

• Inject within 15 minutes before the meal; if necessary, immediately after the meal.

Adult dosing (general starting points—individualize to SMBG/CGM)

• Insulin-naïve Type 2 diabetes
• Start 0.3–0.5 U/kg/day, split BID with breakfast and dinner (e.g., total daily dose 20–30 U → 10–15 U with breakfast + 10–15 U with dinner).
• Alternatively, start 10 U with breakfast and 10 U with dinner, then titrate.
• From basal insulin to premix BID
• If fasting glucose is near goal but A1C elevated → convert to total daily dose ≈ 0.5–0.6 U/kg/day and split BID (AM/PM).
• Practical approach: take current basal dose as ~50% of new total daily dose; give ½ TDD with breakfast + ½ with dinner, then titrate.
• From human 70/30 or other premix to lispro premix
• Unit-to-unit switch at similar frequency (BID or TID), then adjust to glucose targets.
• Type 1 diabetes (selected adults with fixed meals)
• Total daily insulin typically 0.4–1.0 U/kg/day; if using premix, split into BID or TID doses aligned to meals. (Note: many patients with T1D do better on basal-bolus; choose premix only when appropriate.)

Pediatrics

• Use may be considered in selected children/adolescents with stable, predictable meals; individualize dosing (typical total daily insulin 0.5–1.0 U/kg/day distributed to match intake). Many guidelines prefer basal-bolus for pediatric flexibility; specialist supervision advised.

Elderly; renal/hepatic impairment

• Start conservatively (e.g., 0.2–0.3 U/kg/day or lower) and titrate slowly due to higher hypoglycemia risk. Frequent glucose monitoring is essential.

Titration (example, adapt to local protocol)

• If fasting or pre-evening meal glucose above target for 3 consecutive days, increase the preceding dose by 2–4 U (or 10%).
• If hypoglycemia (<70 mg/dL / <3.9 mmol/L) occurs without clear cause, reduce the related dose by 10–20% and reassess.

Administration/handling

• Use U-100 insulin syringes or the corresponding prefilled pen.
• Gently roll and invert the suspension until uniformly cloudy—do not shake vigorously.
• Rotate injection sites (abdomen, thigh, upper arm) to reduce lipodystrophy.
• Do not mix with other insulins or dilute.
• Ensure adequate carbohydrate intake with dosing.

Missed dose

• If close to mealtime, take dose and eat promptly. If a meal is skipped, skip the corresponding dose to avoid hypoglycemia.

Insulin lispro is a rapid-acting analog that binds to the insulin receptor (IR-A and IR-B) on target tissues (liver, muscle, adipose), activating receptor tyrosine kinase activity and downstream PI3K-Akt and MAPK pathways. This acutely promotes GLUT4 translocation and glucose uptake in muscle and adipose tissue, suppresses hepatic gluconeogenesis and glycogenolysis, enhances glycogenesis and lipogenesis, and inhibits lipolysis and ketogenesis. The protamine-complexed lispro fraction forms microcrystals at physiologic pH after SC injection, slowing dissolution and absorption to provide an intermediate-acting basal component, while the uncomplexed lispro delivers rapid prandial coverage. The result is a biphasic profile: early control of post-meal glucose with sustained background activity between doses.

• Absorption / Onset: Rapid-acting lispro component begins within ~10–20 minutes; protamine-complexed fraction has delayed absorption with a later peak.
• Time-to-peak: Early prandial peak ~1–2 hours (lispro); second broader peak ~4–8 hours (protamine component).
• Duration: Up to 18–24 hours overall (ratio- and dose-dependent).
• Bioavailability: Comparable to human insulin given SC; varies by site (abdomen fastest).
• Distribution: Limited volume (vascular/interstitial); minimal CNS penetration; ~0% protein binding in a clinically meaningful sense.
• Metabolism: Proteolytic degradation to peptides/amino acids in liver, kidney, and muscle; not CYP450 mediated.
• Elimination: Metabolites excreted primarily via renal route; insulin clearance reduced in renal impairment.
• Steady state: Achieved within several doses; day-to-day variability influenced by site, temperature, activity, and injection technique.

• Pregnancy: Human experience supports insulin as the preferred therapy for diabetes in pregnancy. Lispro has historically been Category B and is widely used; premixed lispro protamine + lispro can be used when clinically appropriate. Optimize glucose tightly; adjust doses frequently.
• Lactation: Insulin is compatible with breastfeeding; minimal oral bioavailability to the infant (proteolysis in gut). Monitor maternal glucose needs (often reduced postpartum) and infant for signs of hypoglycemia if maternal control is very tight.
• Counseling: Frequent SMBG/CGM, dietetic support, and obstetric-endocrine co-management are recommended.

• Primary: Antidiabetic agent — Insulin analog
• Subclass: Premixed biphasic insulin analog (rapid-acting lispro + intermediate-acting lispro protamine)

• Hypersensitivity to insulin lispro, protamine, or formulation excipients.
• Hypoglycemia (ongoing) — withhold until resolved.
• Use in insulin pumps or IV administration (formulation is a suspension).
• DKA or HHS (requires IV regular insulin with electrolyte management).

• Severe hypoglycemia: Most important risk; educate on recognition (sweating, tremor, confusion) and treatment (fast-acting carbohydrate; glucagon if severe). Increased risk with missed meals, excessive dosing, renal/hepatic impairment, or elderly patients.
• Hypokalemia: Insulin shifts K⁺ intracellularly; monitor when high doses are used or when on K⁺-lowering drugs.
• Fluid retention/heart failure with TZDs: Concomitant pioglitazone/rosiglitazone may cause or worsen edema/CHF—monitor for weight gain, dyspnea.
• Hypersensitivity reactions: Local or systemic (rare anaphylaxis); discontinue if severe.
• Lipodystrophy and cutaneous amyloidosis: Rotate sites to prevent lipohypertrophy/lipoatrophy; injecting into affected areas alters absorption.
• Antibody formation: May alter insulin requirements.
• Visual changes: Rapid glucose improvement can transiently worsen retinopathy symptoms; maintain gradual titration.
• Switching insulins: Any change in type/brand/strength/device requires enhanced monitoring and dose adjustments.
• Driving/operating machinery: Caution if hypoglycemia unawareness or frequent lows.

Very common / common

• Metabolic: Hypoglycemia (dose-dependent; often within peak windows).
• General: Weight gain, peripheral edema (more likely with TZDs).
• Injection site: Pain, erythema, pruritus, induration; lipodystrophy with poor rotation.
• Skin/allergy: Rash, urticaria.

Uncommon

• Electrolytes: Hypokalemia (especially with high doses/IV insulin elsewhere in care).
• Immune: Insulin antibodies affecting dose needs.

Rare/serious

• Anaphylaxis or severe generalized allergy.
• Cutaneous amyloidosis at injection sites.
• Severe hypoglycemia with seizures/coma (overdose, missed meals, renal impairment).

Onset/severity

• Post-dose lows typically occur 1–3 hours after injection (rapid component) and again 4–10 hours (protamine component), varying with dose/ratio/site/activity. Severity correlates with dose, missed meals, and renal function.

Increase hypoglycemia risk / enhance insulin effect

• Alcohol (acute intake), ACE inhibitors, ARBs, salicylates, MAO inhibitors, fluoroquinolones, non-selective beta-blockers (also mask symptoms of hypoglycemia), octreotide (variable), and anabolic agents.

Increase hyperglycemia / reduce insulin effect

• Corticosteroids, sympathomimetics (e.g., albuterol, epinephrine), diuretics (thiazides/loops), niacin, protease inhibitors, atypical antipsychotics, thyroid hormones.

Edema/heart failure risk

• Thiazolidinediones (TZDs): additive fluid retention and potential CHF—monitor closely.

Mechanistic notes

• Not CYP-mediated; interactions largely pharmacodynamic (altered insulin sensitivity, hepatic glucose output, or symptom masking).

• Modern guidelines endorse individualized insulin strategies; premixed analogs remain appropriate when BID/TID fixed meal patterns align with therapy or when simplifying a basal-bolus regimen is necessary.
• Growing use of CGM in insulin-treated T2D supports safer titration and hypoglycemia reduction with premix regimens.
• When intensifying from basal insulin in T2D, options include adding prandial insulin, switching to premix BID/TID, or initiating GLP-1 RA; choice guided by A1C pattern, weight, and hypoglycemia risk.

(No regulatory warnings unique to this combination beyond class warnings for insulins.)

Unopened (vials or prefilled pens)

• Store refrigerated at 2–8°C. Do not freeze. Protect from light.

In use

• Prefilled pens (lispro premix): keep at room temperature (generally below 30°C) and use within 10 days of first use (follow specific device labeling if it states up to 10–14 days). Do not refrigerate the pen in use.
• Vials: may be kept at room temperature or refrigerated; discard 28 days after first puncture.

Handling

• Do not expose to excessive heat or direct sunlight.
• Do not use if the suspension remains clumpy, has particles, or does not redisperse to a uniform cloudy appearance after gentle mixing.
• Do not shake vigorously; roll/invert gently to resuspend before each dose.
• Keep out of reach of children.