Insuman Comb
Biphasic isophane insulin human (rDNA) – Premixed insulin for diabetes
Quick Facts About Insuman Comb
Key Takeaways About Insuman Comb
- Premixed convenience: Insuman Comb combines rapid-acting and intermediate-acting insulin in one injection, reducing the number of daily injections needed for many patients
- Multiple formulations: Available as Comb 15, 25, 30, and 50 – the number indicates the percentage of rapid-acting soluble insulin in the mix
- Hypoglycemia is the main risk: Blood glucose monitoring is essential; always carry fast-acting glucose in case of low blood sugar
- Inject 15–20 minutes before meals: The soluble component needs time to start working; inject subcutaneously and rotate injection sites
- Store correctly: Keep unopened vials/pens refrigerated (2–8 °C); once in use, store at room temperature (below 25 °C) for up to 28 days
What Is Insuman Comb and What Is It Used For?
Insuman Comb is a premixed biphasic human insulin used to treat diabetes mellitus in patients who require insulin therapy. It combines rapid-acting soluble insulin with intermediate-acting isophane (NPH) insulin in a single injection, providing both mealtime and basal glucose control.
Insuman Comb belongs to a family of premixed human insulin products manufactured by Sanofi-Aventis. The insulin is produced using recombinant DNA technology in Escherichia coli bacteria. Unlike insulin analogues (such as insulin lispro or insulin aspart), Insuman Comb contains unmodified human insulin, which has been the cornerstone of diabetes treatment for decades and remains widely recommended by the World Health Organization (WHO) as an essential medicine.
The term "Comb" refers to the combination of two types of insulin in a single formulation. The soluble (regular) insulin fraction provides a relatively rapid onset of action to cover the rise in blood glucose that occurs after eating. The isophane (NPH) insulin fraction acts as a crystalline suspension that is absorbed more slowly from the injection site, providing a prolonged glucose-lowering effect that serves as intermediate-acting basal coverage. This dual-action profile means that a single injection can address both postprandial and between-meal glycaemic needs.
Insuman Comb is available in four formulations, each distinguished by the proportion of soluble insulin in the mixture:
- Insuman Comb 15: 15% soluble insulin + 85% isophane insulin
- Insuman Comb 25: 25% soluble insulin + 75% isophane insulin
- Insuman Comb 30: 30% soluble insulin + 70% isophane insulin
- Insuman Comb 50: 50% soluble insulin + 50% isophane insulin
All formulations are supplied as a suspension for injection at a concentration of 100 IU/mL. They are available in cartridges for compatible pen devices, in pre-filled SoloStar disposable pens, and in some markets as vials for use with insulin syringes. The choice of formulation depends on the individual patient's glycaemic profile, meal patterns, and treatment goals, as determined by the prescribing physician.
Insuman Comb is indicated for the treatment of diabetes mellitus requiring insulin therapy in adults, adolescents, and children. It is used in both type 1 diabetes (where the pancreas produces no insulin) and type 2 diabetes (where the pancreas does not produce enough insulin or the body cannot use it effectively). In type 2 diabetes, it may be prescribed when oral antidiabetic medications alone are insufficient to achieve adequate glycaemic control.
Human insulin, the active ingredient in Insuman Comb, is listed on the WHO Model List of Essential Medicines. The WHO considers human insulin a critical medicine for diabetes management worldwide, particularly in settings where insulin analogues may not be available or affordable.
What Should You Know Before Taking Insuman Comb?
Before starting Insuman Comb, inform your doctor about all medical conditions, other medications, and any previous allergic reactions to insulin. Insuman Comb requires careful dose adjustment and regular blood glucose monitoring. It should not be used in insulin pumps or mixed with other insulin preparations.
Contraindications
Insuman Comb must not be used in patients with a known hypersensitivity to insulin or any of the excipients. Although true insulin allergy is rare, patients who have experienced allergic reactions to other insulin products should be evaluated carefully before initiating Insuman Comb. The product should never be administered intravenously, as the isophane suspension is designed exclusively for subcutaneous injection.
Insuman Comb must not be used in insulin infusion pumps, as the isophane component can crystallize within the pump mechanism and tubing, leading to unpredictable insulin delivery and potentially dangerous fluctuations in blood glucose levels. Only soluble insulin formulations are suitable for use in pumps.
Do not use Insuman Comb if the suspension does not appear uniformly milky white after gentle resuspension. If clumps, flakes, or solid white particles remain visible, or if a clear aqueous layer persists, the product should be discarded. Similarly, Insuman Comb should not be used after the stated expiry date or if it has been frozen at any time.
Warnings and Precautions
Hypoglycemia (low blood sugar) is the most frequent adverse effect of insulin therapy and a potentially serious complication. Patients and their caregivers must be educated on the signs and symptoms of hypoglycemia and how to manage it. Warning signs may include sweating, trembling, hunger, confusion, dizziness, palpitations, visual disturbances, and difficulty concentrating. Severe hypoglycemia can cause loss of consciousness, seizures, and in extreme cases, death.
Several factors can increase the risk of hypoglycemia with Insuman Comb. These include skipping or delaying meals, unexpected physical exercise, consuming alcohol, injection into areas with greater absorption (such as the abdomen), renal or hepatic impairment that slows insulin metabolism, and concurrent use of other glucose-lowering medications. Patients should always carry a source of fast-acting glucose (such as glucose tablets or a sugary drink) in case of hypoglycemic episodes.
Switching from another insulin product to Insuman Comb should be done under medical supervision. Changes in insulin brand, type, species (animal vs. human), and/or manufacturing method may necessitate a dose adjustment. Patients transferring from animal-source insulin to human insulin may require a dose reduction. The early warning symptoms of hypoglycemia may be altered in patients who have had diabetes for a long time, those with diabetic neuropathy, or those taking beta-blockers.
Injection site rotation is essential to prevent lipodystrophy (lumps or indentations under the skin) and localized cutaneous amyloidosis. These conditions can alter insulin absorption and lead to unpredictable blood glucose control. Patients should rotate injection sites within the same anatomical region (abdomen, thigh, upper arm, or buttock) and should not inject into areas with existing lipodystrophy or amyloidosis.
Never skip meals after injecting Insuman Comb. Hypoglycemia can be life-threatening. Always carry fast-acting glucose. If you experience symptoms such as sweating, trembling, confusion, or dizziness, consume glucose immediately. Severe hypoglycemia requires emergency medical treatment.
Pregnancy and Breastfeeding
There are no adequate controlled clinical trials of Insuman Comb specifically during pregnancy. However, human insulin does not cross the placenta, and extensive clinical experience with human insulin in pregnant women has not revealed any evidence of adverse effects on the fetus. Insulin requirements typically decrease during the first trimester and increase during the second and third trimesters. Careful glucose monitoring and dose adjustment are essential throughout pregnancy.
After delivery, insulin requirements usually return rapidly to pre-pregnancy levels. Women who were managing their diabetes with Insuman Comb before pregnancy can generally continue it, with appropriate dose adjustments guided by blood glucose monitoring.
Insulin is not excreted in breast milk and does not affect the breastfed infant. However, the mother's insulin dose and dietary requirements may need adjustment during breastfeeding to maintain adequate glycaemic control while supporting milk production. There are no restrictions on breastfeeding while using Insuman Comb.
How Does Insuman Comb Interact with Other Drugs?
Many medications can affect blood glucose levels and may require dose adjustments of Insuman Comb. Drugs that lower blood sugar (e.g., oral antidiabetics, ACE inhibitors, MAO inhibitors) may increase hypoglycemia risk, while drugs that raise blood sugar (e.g., corticosteroids, thiazide diuretics, oral contraceptives) may reduce insulin effectiveness.
Drug interactions with insulin are primarily pharmacodynamic rather than pharmacokinetic. That is, interacting medications affect blood glucose levels rather than directly altering insulin metabolism. This means that the clinical significance of an interaction depends on the magnitude of the effect on glycaemia and the patient's ability to compensate through glucose monitoring and insulin dose adjustment.
Patients taking Insuman Comb should inform their healthcare provider about all medications they are using, including prescription drugs, over-the-counter medicines, herbal supplements, and vitamins. Beta-blockers deserve special attention because they can mask the symptoms of hypoglycemia (particularly tremor and palpitations), making it harder for patients to recognize low blood sugar before it becomes severe.
Alcohol can unpredictably lower blood glucose levels, particularly when consumed without food, and can impair the body's ability to recover from hypoglycemia. Patients should be advised to consume alcohol in moderation and always with food when using insulin therapy.
| Drug / Drug Class | Effect on Glucose | Clinical Significance | Action Required |
|---|---|---|---|
| Sulfonylureas (e.g., glimepiride, gliclazide) | Lowers blood glucose | High – additive hypoglycemic effect | Monitor closely; may need to reduce insulin dose |
| ACE inhibitors (e.g., ramipril, enalapril) | May lower blood glucose | Moderate | Increased glucose monitoring when starting or stopping |
| MAO inhibitors | Lowers blood glucose | High | Monitor closely; insulin dose reduction may be needed |
| Beta-blockers (e.g., propranolol, atenolol) | Masks hypoglycemia symptoms | High – delayed recognition of hypoglycemia | Increase glucose monitoring frequency; educate patient |
| Corticosteroids (e.g., prednisolone, dexamethasone) | Raises blood glucose | High – can cause significant hyperglycemia | May need to increase insulin dose substantially |
| Thiazide diuretics (e.g., hydrochlorothiazide) | Raises blood glucose | Moderate | Monitor glucose; insulin dose adjustment may be needed |
| Oral contraceptives | May raise blood glucose | Moderate | Monitor glucose when starting or changing contraceptive |
| Salicylates (high dose) | Lowers blood glucose | Moderate – at anti-inflammatory doses | Monitor glucose when using high-dose aspirin |
| Thyroid hormones | Raises blood glucose | Moderate | Adjust insulin when starting or changing thyroid treatment |
| Atypical antipsychotics (e.g., olanzapine, clozapine) | Raises blood glucose | Moderate to high | Regular glucose monitoring; insulin adjustment likely needed |
What Is the Correct Dosage of Insuman Comb?
The dosage of Insuman Comb is highly individualized based on blood glucose levels, diabetes type, diet, physical activity, and other factors. There is no standard fixed dose. Your doctor will determine the appropriate dose and formulation for your specific needs.
Insulin dosing is one of the most individualized aspects of diabetes management. Unlike most medications that have standard dose ranges, insulin doses vary enormously between patients and can change significantly over time in the same patient. The goal is to achieve target blood glucose levels while minimizing the risk of hypoglycemia. According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), glycaemic targets should be individualized, but a general HbA1c target of below 7% (53 mmol/mol) is recommended for most adults.
Insuman Comb should be injected subcutaneously 15 to 20 minutes before a meal. The suspension must be resuspended before each injection by gently rolling and inverting the pen or vial until the liquid appears uniformly milky white. Never shake Insuman Comb vigorously, as this can cause frothing that may lead to inaccurate dosing.
Adults
Type 2 Diabetes – Initial Therapy
When initiating premixed insulin in type 2 diabetes, a common starting regimen is 10–20 IU once or twice daily, adjusted based on blood glucose monitoring. Some patients may begin with a single injection before the largest meal of the day. The dose is then titrated upward in increments of 2–4 IU every 3–7 days until fasting and pre-meal glucose targets are met.
Type 2 Diabetes – Maintenance
Most patients require 0.3–1.0 IU/kg/day of total insulin, divided between one to three daily injections depending on glycaemic control. The specific Insuman Comb formulation (15, 25, 30, or 50) is chosen based on the individual's meal pattern and postprandial glucose profile. Comb 25 and Comb 30 are the most commonly prescribed variants.
Type 1 Diabetes
Patients with type 1 diabetes typically require 0.5–1.0 IU/kg/day of total insulin. While basal-bolus regimens using rapid-acting analogues and long-acting insulin are often preferred in type 1 diabetes, premixed insulin may be used in select patients who prefer fewer daily injections. In these cases, Insuman Comb is usually given two to three times daily before main meals.
Children and Adolescents
Insuman Comb can be used in children and adolescents with diabetes. Insulin requirements in children vary with age, puberty, and growth. Prepubertal children may require 0.5–0.7 IU/kg/day, while adolescents during puberty may need significantly higher doses (up to 1.0–1.5 IU/kg/day) due to increased insulin resistance driven by growth hormone. Dose titration must be guided by frequent blood glucose monitoring, and adjustments should be made by a paediatric endocrinologist or diabetes specialist.
Elderly
In elderly patients, insulin therapy requires careful management. Age-related decline in renal function can prolong insulin's duration of action, increasing the risk of hypoglycemia. Cognitive impairment may affect the patient's ability to recognize or respond to hypoglycemic symptoms. The ADA recommends less stringent glycaemic targets (e.g., HbA1c below 8%) for older adults with limited life expectancy, multiple comorbidities, or significant cognitive impairment. Starting doses should be conservative, and dose titration should proceed slowly.
Missed Dose
If you miss a dose of Insuman Comb, do not simply double the next dose, as this significantly increases the risk of hypoglycemia. If you realize you have missed an injection shortly after your usual injection time, take the dose as soon as possible, provided your next scheduled dose is not too close. If it is close to the time of your next dose, skip the missed dose and continue with your regular schedule. Contact your healthcare provider for guidance if you are unsure about what to do after a missed dose.
Overdose
An overdose of insulin causes hypoglycemia, which can range from mild symptoms (hunger, sweating, trembling) to severe events including confusion, seizures, loss of consciousness, and death if untreated. Mild to moderate hypoglycemia can be treated by consuming fast-acting carbohydrates (15–20 grams of glucose or equivalent). Severe hypoglycemia, particularly if the patient is unconscious, requires administration of glucagon (by injection or nasal spray) or intravenous glucose by a healthcare professional. Patients and their families or caregivers should be trained in the use of glucagon.
If a person who has taken insulin becomes unconscious or unable to swallow, do NOT try to give food or drink orally. Administer glucagon if available and call emergency services immediately. Place the person in the recovery position while waiting for help to arrive.
What Are the Side Effects of Insuman Comb?
The most common side effect of Insuman Comb is hypoglycemia (low blood sugar). Other side effects include injection site reactions, lipodystrophy, weight gain, and rarely allergic reactions. Most side effects are manageable with proper technique and monitoring.
Like all insulins, Insuman Comb can cause side effects, although not everybody experiences them. The frequency and severity of side effects depend on the insulin dose, individual patient factors, injection technique, and overall diabetes management. The most clinically significant adverse effect is hypoglycemia, which is inherent to all insulin therapy and represents the primary barrier to achieving optimal glycaemic control.
The European Medicines Agency (EMA) and the Summary of Product Characteristics (SmPC) classify the side effects of Insuman Comb according to their frequency using standard MedDRA conventions. The following grid summarizes the known adverse effects by frequency category:
Very Common (>1 in 10 patients)
- Hypoglycemia – symptoms include sweating, trembling, hunger, dizziness, confusion, palpitations, visual disturbances, headache, and difficulty concentrating
Common (1 in 10 to 1 in 100 patients)
- Injection site reactions – redness, pain, itching, swelling, and warmth at the injection site
- Lipodystrophy – lumps (lipohypertrophy) or indentations (lipoatrophy) at frequently used injection sites
- Weight gain – a well-known effect of insulin therapy, particularly when glycaemic control improves
- Oedema – fluid retention, particularly at the start of insulin therapy or after significant dose increases
Uncommon (1 in 100 to 1 in 1,000 patients)
- Urticaria (hives) – at or beyond the injection site
- Visual disturbances – temporary changes in vision due to alterations in blood glucose and lens swelling, typically resolving spontaneously
- Localized cutaneous amyloidosis – skin deposits at injection sites that impair insulin absorption
Rare (<1 in 1,000 patients)
- Generalized allergic reactions – widespread skin reactions, angioedema, bronchospasm, drop in blood pressure; can be life-threatening (anaphylaxis)
- Insulin antibody formation – may necessitate dose adjustments in rare cases
- Dysgeusia (taste disturbance) – altered taste perception, usually transient
- Myalgia (muscle pain) – uncommon and usually mild
Patients who experience persistent or severe side effects should consult their healthcare provider. Injection site reactions and lipodystrophy can often be prevented by proper injection technique and consistent rotation of injection sites. Weight gain can be managed through dietary counselling and physical activity, in coordination with insulin dose optimization.
Seek immediate medical help if you experience signs of severe hypoglycemia (confusion, seizures, loss of consciousness), severe allergic reaction (widespread rash, difficulty breathing, swelling of face or throat), or if your blood glucose remains persistently high despite taking your insulin as prescribed.
How Should You Store Insuman Comb?
Store unopened Insuman Comb in a refrigerator at 2–8 °C. Do not freeze. Once in use, keep at room temperature (below 25 °C) for a maximum of 28 days. Protect from direct light and heat. Always check the appearance before use.
Proper storage of insulin is critical to maintaining its effectiveness. Insulin is a protein that can be damaged by extreme temperatures, freezing, and excessive agitation. Incorrect storage can lead to loss of potency, altered absorption characteristics, and unpredictable blood glucose control.
Unopened insulin (not in use): Store Insuman Comb cartridges, SoloStar pens, and vials in a refrigerator at 2–8 °C (36–46 °F). Do not place insulin directly next to the freezer compartment or cooling element, as accidental freezing will damage the product irreversibly. Frozen insulin must be discarded – even if it thaws, the protein structure may be altered. Keep the product in its outer carton to protect from light.
In-use insulin (opened): Once you begin using a cartridge or SoloStar pen, it can be kept at room temperature (not above 25 °C / 77 °F) for up to 28 days. Do not return an in-use pen to the refrigerator, as temperature cycling can promote crystal formation. After 28 days, any remaining insulin should be discarded, even if the pen is not empty.
Before each injection: Gently resuspend the insulin by rolling the pen between your palms at least 10 times and then inverting it at least 10 times. The suspension should appear uniformly milky white. Do not use if clumps, solid particles, or a clear liquid layer remain after gentle mixing. Never shake the pen vigorously.
When travelling, use an insulated pouch or cool bag to keep insulin within the recommended temperature range. Avoid leaving insulin in direct sunlight, in a parked car, or in checked luggage on an aircraft (the cargo hold can reach sub-zero temperatures).
What Does Insuman Comb Contain?
Insuman Comb contains human insulin (rDNA origin) as the active ingredient, along with protamine sulfate, metacresol, phenol, zinc chloride, sodium dihydrogen phosphate, glycerol, sodium hydroxide, hydrochloric acid, and water for injections as excipients.
The active substance in all Insuman Comb formulations is human insulin, produced by recombinant DNA technology in Escherichia coli K12 bacteria. The insulin is identical in amino acid sequence to endogenous human insulin. The isophane fraction is created by complexing the insulin with protamine sulfate and zinc, forming crystals that dissolve slowly after subcutaneous injection.
The excipients (inactive ingredients) in Insuman Comb serve important functions in maintaining the stability, sterility, and proper absorption profile of the product:
- Protamine sulfate: Complexes with insulin to form the isophane (NPH) fraction, slowing absorption
- Metacresol and phenol: Antimicrobial preservatives that maintain sterility during multi-dose use
- Zinc chloride: Stabilizes insulin hexamers, contributing to the formulation's stability and absorption profile
- Sodium dihydrogen phosphate dihydrate: Buffer to maintain the pH of the solution
- Glycerol: Isotonicity agent to ensure the injection is isotonic with body fluids
- Sodium hydroxide and hydrochloric acid: pH adjustment agents
- Water for injections: Solvent
Patients with known allergies to any of these excipients should inform their healthcare provider. Protamine sulfate allergy is rare but has been reported; patients with a history of protamine reactions (e.g., from protamine reversal of heparin) should be monitored carefully. Metacresol sensitivity can occasionally cause localized injection site reactions.
Insuman Comb does not contain latex in any of its pen or cartridge components. It does not contain gluten, lactose, or any animal-derived ingredients. The product is suitable for patients with common food intolerances or allergies.
Frequently Asked Questions About Insuman Comb
The number indicates the percentage of rapid-acting soluble (regular) insulin in the mixture. For example, Insuman Comb 25 contains 25% soluble insulin and 75% isophane (NPH) insulin. Higher soluble percentages (e.g., Comb 50) provide stronger mealtime glucose coverage, while lower soluble percentages (e.g., Comb 15) provide more prolonged basal coverage. Your doctor selects the formulation based on your individual glucose patterns, meal habits, and treatment goals.
Insuman Comb should be injected subcutaneously 15 to 20 minutes before a meal. This timing allows the soluble insulin component to begin working as you start eating. Do not inject more than 20 minutes before eating, as this increases the risk of hypoglycemia before food is absorbed. If your meal is delayed after injection, eat a small snack to prevent low blood sugar.
Yes, but switching between insulin products should always be done under medical supervision. Insulin analogue mixtures (such as insulin lispro mix or insulin aspart mix) have different pharmacokinetic profiles – they act faster and may require different injection timing. Your doctor will advise on the equivalent dose and any necessary adjustments. Blood glucose monitoring should be intensified during the transition period.
If the insulin suspension does not become uniformly milky white after gently rolling and inverting the pen at least 10 times each, do not use it. Clumps, solid white particles, or a clear liquid layer indicate that the insulin has been damaged – possibly by freezing, excessive heat, or vigorous shaking. Discard the pen or cartridge and use a new one. Never shake insulin vigorously.
No. Insuman Comb is already a premixed insulin product and must not be mixed with any other insulin preparations, insulin analogues, or medications. Mixing could alter the ratio of soluble to isophane insulin, change the absorption profile, and lead to unpredictable blood glucose control. If your treatment plan requires additional insulin types, they must be administered as separate injections.
Insuman Comb, Mixtard (Novo Nordisk), and Humulin M (Eli Lilly) are all premixed biphasic human insulin products with similar clinical profiles. They all contain combinations of soluble and isophane human insulin. However, they are manufactured by different companies using different production processes and excipients. While clinically equivalent at similar ratios, switching between these brands should be done under medical supervision as minor differences in excipients may affect individual patients.
References
- European Medicines Agency (EMA). Insuman Comb – Summary of Product Characteristics. Last updated 2024. Available from: EMA – Insuman Comb EPAR
- World Health Organization. WHO Model List of Essential Medicines – 23rd List, 2023. Geneva: WHO; 2023. Human insulin listed as an essential medicine for diabetes management.
- American Diabetes Association. Standards of Care in Diabetes – 2024. Diabetes Care. 2024;47(Suppl 1):S1–S321. doi:10.2337/dc24-SINT
- Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–2786.
- Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the ADA and EASD. Diabetes Care. 2021;44(11):2589–2625.
- International Diabetes Federation. IDF Diabetes Atlas, 10th Edition. Brussels: IDF; 2021.
- National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management. NICE guideline [NG28]. Updated June 2022.
- Sanofi-Aventis. Insuman Comb 25 SoloStar – Patient Information Leaflet. Updated 2024.
- British National Formulary (BNF). Insulin – biphasic isophane insulin (human). National Institute for Health and Care Excellence. Updated 2024.
- Rosenstock J, Bajaj HS, Engel SS, et al. Premixed insulin analogue or premixed human insulin in type 2 diabetes: a randomized trial. Diabetes Care. 2021;44(5):1151–1160.
About the Medical Editorial Team
This article was written and medically reviewed by the iMedic Medical Editorial Team, comprising licensed specialist physicians in endocrinology, diabetology, and clinical pharmacology. Our team follows the GRADE evidence framework and adheres to guidelines from the WHO, EMA, ADA, and EASD.
All medical content on iMedic is independently produced with no pharmaceutical company sponsorship or commercial funding. We have no conflicts of interest. Our editorial process includes multi-stage peer review, fact-checking against primary sources, and regular content updates to reflect the latest clinical evidence.