Protaphane FlexPen: Uses, Dosage & Side Effects
An intermediate-acting isophane (NPH) human insulin in a pre-filled disposable injection pen, used for basal blood glucose control in type 1 and type 2 diabetes mellitus
Protaphane FlexPen is a pre-filled disposable injection pen containing isophane (NPH) human insulin 100 IU/ml, manufactured by Novo Nordisk. Known internationally as Protaphane, Insulatard, Humulin N or Novolin N depending on the market, this intermediate-acting insulin provides basal (background) blood glucose control in adults, adolescents and children with diabetes mellitus. After subcutaneous injection, it begins lowering blood glucose in approximately 1.5 hours, peaks between 4 and 12 hours, and has a total duration of action up to 24 hours. Insulin is included on the WHO Model List of Essential Medicines, and the FlexPen is one of the most widely used insulin delivery devices in the world, valued for its simplicity, portability and accurate dose delivery.
Quick Facts: Protaphane FlexPen
Key Takeaways
- Protaphane FlexPen delivers isophane (NPH) human insulin in a pre-filled, disposable pen of 3 ml (100 IU/ml, 300 IU total) and is used for basal blood glucose control in type 1 and type 2 diabetes.
- Hypoglycaemia (low blood sugar) is the most frequent adverse effect; patients must learn early warning symptoms and always carry fast-acting carbohydrates such as glucose tablets.
- The suspension must be gently rolled and inverted at least 20 times before every injection until it appears uniformly white and cloudy – never shake the pen vigorously.
- The FlexPen delivers doses from 1 to 60 IU in 1-unit increments and must only be used for subcutaneous injection (never intravenously or in an insulin pump).
- Unopened pens are stored in the refrigerator at 2–8°C; once in use, a pen can be kept at room temperature (below 30°C) for up to 6 weeks and must then be discarded.
What Is Protaphane FlexPen and What Is It Used For?
Protaphane FlexPen is a pre-filled, disposable insulin injection pen manufactured by Novo Nordisk that contains 3 ml of isophane human insulin at a concentration of 100 international units per millilitre (100 IU/ml), giving a total of 300 IU per pen. The active substance, insulin human (isophane), is produced using recombinant DNA technology in Saccharomyces cerevisiae (baker’s yeast). The insulin is then complexed with protamine sulphate to form small crystals – the basis of the isophane or “Neutral Protamine Hagedorn” (NPH) formulation. This protamine complexation is the key pharmaceutical feature that delays insulin absorption from the subcutaneous injection site, producing a slower onset of action and a prolonged duration of effect compared with regular soluble human insulin or rapid-acting insulin analogues.
In many European countries the product is sold as Protaphane or Protaphane FlexPen, while in other markets the same insulin is marketed by Novo Nordisk under the brand name Insulatard. Competitor products with the same active substance include Humulin N and Novolin N (Eli Lilly), which are biosimilar intermediate-acting NPH insulins. Because the active substance and pharmacology are essentially identical across these brands, the clinical information in this article also applies to those products, but device-specific instructions and strengths may differ.
After subcutaneous injection, Protaphane begins to lower blood glucose within approximately 1.5 hours. Its maximum blood-glucose-lowering effect (peak) occurs between 4 and 12 hours after injection, and the total duration of action extends up to approximately 24 hours. This pharmacokinetic profile makes Protaphane suitable as a basal insulin, providing background glucose control between meals and during sleep. It is important to understand, however, that the time course of insulin action varies considerably between individuals and even within the same person from day to day, partly depending on the injection site, injection technique, dose size, local blood flow, ambient temperature and level of physical activity.
Protaphane FlexPen is indicated for the treatment of diabetes mellitus in patients who require insulin. This includes:
- Type 1 diabetes mellitus: All people with type 1 diabetes require exogenous insulin for survival because their pancreatic beta cells have been destroyed by an autoimmune process. Protaphane is typically used as the basal component of a multiple daily injection (MDI) regimen, combined with a rapid-acting insulin at mealtimes.
- Type 2 diabetes mellitus: When lifestyle measures and oral antidiabetic medications are no longer sufficient to achieve adequate glycaemic control, basal insulin such as Protaphane may be added to the regimen. It is often initiated as a single daily injection at bedtime alongside existing oral therapy.
- Gestational and pre-gestational diabetes: Protaphane can be used during pregnancy when diet alone is not enough. Insulin does not cross the placenta and is considered safe for both mother and foetus.
- Diabetes in children and adolescents: Protaphane is approved for use in children of all ages. NPH insulin has a long track record in paediatric diabetes care.
From a global health perspective, insulin is on the WHO Model List of Essential Medicines, reflecting its critical importance for the survival and wellbeing of hundreds of millions of people worldwide. According to the International Diabetes Federation (IDF) Diabetes Atlas, approximately 537 million adults (aged 20–79) were living with diabetes in 2021, a number projected to rise to 783 million by 2045. NPH insulin preparations such as Protaphane remain one of the most widely used basal insulin options globally, particularly in low- and middle-income countries where they offer a cost-effective alternative to newer long-acting analogues.
The FlexPen is a pre-filled, disposable injection pen that is thrown away when empty. It allows dose selection from 1 to 60 IU in 1-unit increments, with clearly visible dose numbers and an audible click for each unit. It does not require cartridge changes, making it simpler for many patients – especially older adults, patients with visual impairment, and those new to insulin therapy. A fresh, sterile needle (NovoFine or NovoTwist) must be attached for every injection.
What Should You Know Before Using Protaphane FlexPen?
Before starting or continuing therapy with Protaphane FlexPen, several important considerations must be addressed to ensure safe and effective insulin use. Patient education, proper device handling and ongoing clinical review are cornerstones of successful insulin therapy. The FlexPen device is designed for patient self-administration, but first-time use should always be demonstrated and supervised by a qualified diabetes educator, nurse or physician.
Contraindications
There are specific situations in which Protaphane FlexPen must not be used. Understanding these absolute contraindications is critical for safe insulin therapy:
- Hypoglycaemia: Protaphane must never be administered when the patient is already hypoglycaemic (blood glucose is too low). Administering additional insulin during hypoglycaemia can cause severe, life-threatening hypoglycaemia with loss of consciousness, seizures, or death.
- Hypersensitivity: Do not use Protaphane FlexPen if you have a known hypersensitivity to human insulin, protamine sulphate, or any of the other ingredients (metacresol, phenol, zinc chloride, glycerol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, or water for injection).
- Intravenous or intramuscular administration: Protaphane must never be administered intravenously or intramuscularly. Its isophane (NPH) suspension formulation is designed exclusively for subcutaneous injection. Intravenous administration of a suspension can lead to severe hypoglycaemia and other complications.
- Insulin infusion pumps: Protaphane must not be used in continuous subcutaneous insulin infusion (CSII) pumps. Only clear, soluble insulin preparations (such as insulin aspart or insulin lispro) are suitable for pump therapy.
- Damaged pen or abnormal appearance: Do not use a FlexPen that has been damaged, frozen, exposed to extreme heat, or that shows an abnormal appearance after resuspension (clumps, frost, discolouration, or remaining clear).
Warnings and Precautions
Hypoglycaemia is the most frequent adverse effect of insulin therapy and can be life-threatening if severe. Symptoms include sweating, palpitations, tremor, hunger, confusion, drowsiness, difficulty speaking, visual disturbances, and in severe cases, loss of consciousness or seizures. Always carry a source of fast-acting carbohydrates (glucose tablets, fruit juice, regular fizzy drink). Ensure that family members, caregivers and close contacts know how to recognise and treat hypoglycaemia, including how to administer glucagon in an emergency.
Several important warnings and precautions apply to the use of Protaphane FlexPen. These should be discussed with your diabetes care team and revisited whenever your clinical situation changes:
- Dose accuracy and label verification: Always check the insulin label and pen colour before each injection. Confusion between different insulins (e.g. injecting a rapid-acting insulin instead of Protaphane, or vice versa) is a known cause of serious hypo- or hyperglycaemic events. Protaphane FlexPen pens have a distinctive colour scheme to help differentiate them from other Novo Nordisk insulins such as NovoRapid FlexPen or Levemir FlexPen.
- Resuspension before every injection: Before each injection, the FlexPen must be gently rolled between the palms and then inverted (turned upside down and back) at least 20 times until the liquid appears uniformly white and cloudy. Do not use the pen if it remains clear, shows clumps, flakes, or has a frosted appearance. Vigorous shaking must be avoided as it can denature the insulin and cause foaming.
- Injection site rotation: Injection sites should be rotated within the same anatomical area (abdomen, thigh, upper arm, or buttock) from one injection to the next to reduce the risk of lipodystrophy (abnormal thickening or thinning of fat tissue) and cutaneous amyloidosis. Injecting repeatedly into the same small area can cause lumps that delay insulin absorption and destabilise blood glucose.
- Renal or hepatic impairment: Patients with kidney or liver disease often have reduced insulin requirements due to altered metabolism and clearance. Close blood glucose monitoring is essential, and dose adjustments should be made under medical supervision.
- Intercurrent illness: Illness, particularly infections with fever, may increase insulin requirements. Nausea, vomiting and reduced food intake during illness may in contrast decrease insulin needs. Patients should never stop insulin entirely during illness (especially in type 1 diabetes) as this can lead to diabetic ketoacidosis (DKA), a life-threatening emergency. Agree a “sick-day plan” with your diabetes team in advance.
- Transfer from another insulin: Switching from another type, brand, manufacturer or device to Protaphane FlexPen may require dose adjustment. Transfers should be performed under medical supervision with intensified blood glucose monitoring during the first weeks.
- Thiazolidinediones (glitazones): When used with thiazolidinediones (pioglitazone), insulin may increase the risk of heart failure. Patients should report unusual weight gain, swelling, or shortness of breath to their doctor.
- Driving and operating machinery: Hypoglycaemia can impair concentration and reaction time. Patients – particularly those with hypoglycaemia unawareness – should check their blood glucose before driving and carry fast-acting carbohydrates. National driving regulations may impose additional rules on people with insulin-treated diabetes.
- Travel across time zones: Crossing several time zones can disrupt insulin schedules and meal times. Contact your diabetes team in advance to plan dose timing adjustments.
Pregnancy and Breastfeeding
Protaphane FlexPen can be used during pregnancy. Human insulin does not cross the placenta and does not cause harm to the developing foetus. Adequate glycaemic control is essential throughout pregnancy because both hypoglycaemia and hyperglycaemia during pregnancy carry risks for mother and baby. Insulin requirements typically decrease during the first trimester (with an increased risk of hypoglycaemia) and increase during the second and third trimesters due to the insulin-resistant effect of placental hormones. After delivery, insulin requirements usually return rapidly to pre-pregnancy levels – often within 24–48 hours – which requires close monitoring to avoid post-partum hypoglycaemia.
Insulin treatment during breastfeeding does not pose a risk to the nursing infant. Any insulin ingested through breast milk is broken down in the infant’s gastrointestinal tract and is not absorbed in an active form. However, breastfeeding mothers often experience changes in insulin requirements and may need to reduce their dose or adjust mealtime carbohydrate intake to avoid hypoglycaemia, especially during or shortly after feeds.
Women who are pregnant or planning to become pregnant should work closely with their diabetes care team to optimise glycaemic control both before and throughout pregnancy. Uncontrolled diabetes during pregnancy significantly increases the risk of congenital malformations, macrosomia (large baby), birth complications, neonatal hypoglycaemia and pre-eclampsia.
Special Populations
Protaphane can be used across the age spectrum, but certain groups need additional consideration:
- Elderly patients: Older adults have a higher baseline risk of severe hypoglycaemia, falls and cardiovascular events. Glycaemic targets are often individualised to be less stringent (for example, HbA1c 7.5–8.0%) to minimise hypoglycaemia risk. The ease of use of the FlexPen makes it suitable for many older patients, but manual dexterity and vision should be assessed.
- Children: Protaphane is approved in children of all ages. Paediatric dosing requires specialist paediatric diabetes supervision because insulin needs change with growth, puberty and activity.
- Patients with visual impairment: The FlexPen has large, clearly visible numbers and audible dose clicks (one click per unit), but patients with severe visual impairment may benefit from the InnoLet device, which is specifically designed for them.
How Does Protaphane FlexPen Interact with Other Drugs?
Protaphane interacts with a wide range of medications. These interactions can either enhance (potentiate) the blood-glucose-lowering effect of insulin, increasing the risk of hypoglycaemia, or diminish it, potentially causing hyperglycaemia. Understanding these interactions is essential for safe and effective diabetes management. Whenever a new medication is started, stopped, or changed in dose, blood glucose monitoring should be intensified and the insulin dose may need to be adjusted under medical supervision.
Major Interactions (Potentiation of Insulin Effect)
The following medications may increase the blood-glucose-lowering effect of Protaphane, thereby increasing the risk of hypoglycaemia. When starting or increasing the dose of these medications, the Protaphane dose may need to be reduced:
| Drug / Drug Class | Mechanism | Clinical Significance |
|---|---|---|
| Oral antidiabetics (metformin, sulfonylureas, SGLT2 inhibitors, DPP-4 inhibitors) | Additive blood-glucose-lowering effect | High – common combination; monitor FBG and HbA1c closely |
| GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) | Enhance insulin secretion and slow gastric emptying | High – insulin dose often requires reduction of 10–20% at initiation |
| MAO inhibitors (phenelzine, tranylcypromine) | May increase insulin sensitivity | Moderate – monitor blood glucose |
| ACE inhibitors (enalapril, ramipril, lisinopril) | May improve insulin sensitivity | Moderate – especially during initiation or dose changes |
| Salicylates (high-dose aspirin) | Reduce hepatic glucose production | Moderate – at analgesic/anti-inflammatory doses (>2 g/day) |
| Non-selective beta-blockers (propranolol, nadolol) | Mask hypoglycaemic symptoms and delay recovery | High – prefer cardioselective beta-blockers where possible |
| Alcohol | Inhibits hepatic gluconeogenesis | High – can cause prolonged, severe, delayed hypoglycaemia (up to 24 h) |
| Fibrates (fenofibrate, gemfibrozil) | May improve insulin sensitivity | Low to moderate – monitor blood glucose on initiation |
| Anabolic steroids (testosterone) | Increase insulin sensitivity | Moderate – especially at supraphysiological doses |
Interactions That Reduce Insulin Effect (Hyperglycaemia Risk)
The following medications may reduce the blood-glucose-lowering effect of Protaphane, potentially leading to hyperglycaemia. When starting these medications, the Protaphane dose may need to be increased:
| Drug / Drug Class | Mechanism | Clinical Significance |
|---|---|---|
| Corticosteroids (prednisolone, dexamethasone) | Increase hepatic glucose production and reduce insulin sensitivity | High – significant dose increase often needed, especially at high steroid doses |
| Thyroid hormones (levothyroxine) | Increase glucose absorption and gluconeogenesis | Moderate – monitor when initiating or titrating |
| Thiazide diuretics (hydrochlorothiazide, indapamide) | Reduce insulin secretion and sensitivity, particularly at higher doses | Moderate – dose-dependent effect |
| Sympathomimetics (salbutamol, terbutaline, adrenaline) | Stimulate glycogenolysis and gluconeogenesis | Moderate – especially with systemic use or during acute exacerbations |
| Growth hormone (somatotropin) | Counter-regulatory hormone opposing insulin action | Moderate – insulin dose may need to be increased |
| Oral contraceptives | May reduce insulin sensitivity | Low to moderate – monitor blood glucose |
| Danazol | Androgenic effects reducing glucose tolerance | Moderate – monitor blood glucose when starting |
| Atypical antipsychotics (olanzapine, clozapine) | Impair insulin sensitivity and promote weight gain | High – significant metabolic consequences |
| Protease inhibitors (antiretrovirals) | Reduce insulin sensitivity | Moderate – monitor glucose in patients with HIV |
Non-selective beta-blockers (such as propranolol) can mask the warning signs of hypoglycaemia, particularly tachycardia and tremor, making it harder for patients to recognise low blood sugar. Cardioselective beta-blockers (such as metoprolol or bisoprolol) are generally preferred in patients with diabetes, although they may still partially mask symptoms at high doses. All patients taking beta-blockers with insulin should be counselled to rely on alternative hypoglycaemic warning signs such as sweating, hunger and difficulty concentrating.
Octreotide, lanreotide, and somatostatin analogues may alter glucose metabolism in either direction. Clonidine, reserpine and lithium have been reported to modify the action of insulin inconsistently. As a general rule, any new prescription, over-the-counter product, or herbal supplement should be discussed with your diabetes team, with intensified glucose monitoring for at least two weeks after initiation.
What Is the Correct Dosage of Protaphane FlexPen?
Protaphane dosing is always individualised. The target blood glucose levels and dosing schedule are set by the healthcare provider in collaboration with the patient. Factors that influence the optimal dose include type of diabetes, body weight, blood glucose monitoring results, HbA1c, concomitant medications, dietary habits, level of physical activity and the presence of other medical conditions. Insulin doses are measured in International Units (IU), and the FlexPen dial allows selection from 1 to 60 IU in 1-unit increments. If a single dose exceeds 60 IU, the injection must be divided between two pens or, more commonly, split into two separate injections at different times.
Adults
Type 2 Diabetes – Initiation of Basal Insulin
When adding Protaphane FlexPen to oral antidiabetic therapy, a typical starting dose is 10 IU once daily at bedtime, or alternatively 0.1–0.2 IU/kg/day. The dose is then titrated (gradually increased) based on fasting blood glucose (FBG) measurements, typically by 2–4 IU every 3–7 days until the target FBG is achieved – usually 4.0–7.0 mmol/L (70–130 mg/dL), depending on individual targets agreed with the diabetes team.
Type 1 Diabetes – Basal-Bolus Regimen
Total daily insulin requirements in type 1 diabetes are typically 0.5–1.0 IU/kg/day (may be higher during puberty, pregnancy or intercurrent illness). In a basal-bolus regimen, approximately 40–60% of the total daily dose is delivered as Protaphane (usually split into two injections: morning and bedtime), with the remaining 40–60% given as rapid-acting insulin before meals. The exact split depends on the individual’s glucose patterns, meal times, physical activity and lifestyle.
Type 2 Diabetes – Twice-Daily Regimen
Some patients with type 2 diabetes may require twice-daily Protaphane (morning and bedtime) when once-daily dosing does not provide adequate 24-hour glucose control. The total daily dose is typically divided with approximately two-thirds in the morning and one-third at bedtime, though this ratio is adjusted based on individual blood glucose patterns. Twice-daily NPH schedules must always include a meal or snack at the time of peak insulin action (4–12 hours after injection) to avoid hypoglycaemia.
Children and Adolescents
Paediatric Dosing
Protaphane FlexPen is approved for use in children of all ages. Paediatric dosing follows the same principles as in adults, with weight-based dosing. Prepubertal children typically require 0.7–1.0 IU/kg/day total insulin, while adolescents during puberty may require higher doses of 1.0–2.0 IU/kg/day due to increased insulin resistance driven by growth hormones. Basal insulin (Protaphane) generally accounts for 40–60% of total daily insulin. The 1-unit dose increments of the FlexPen allow precise dosing in small children. Paediatric insulin dosing must always be supervised by a specialist paediatric diabetes team.
Elderly Patients
Insulin therapy in elderly patients requires careful individualisation. Older adults are at increased risk of hypoglycaemia, which can be particularly dangerous due to the risk of falls, cardiovascular events and cognitive impairment. Glycaemic targets are typically less stringent (for example, an HbA1c target of 7.5–8.0% or 58–64 mmol/mol may be appropriate rather than the standard target of below 7.0%). Blood glucose monitoring should be performed frequently, and dose adjustments should be gradual. The ergonomic design and large numbers of the FlexPen make it suitable for elderly patients with reduced vision or dexterity, though some may benefit from devices with even larger displays such as the InnoLet.
Patients with Renal or Hepatic Impairment
In patients with kidney disease, insulin clearance is reduced, which may lower total insulin requirements. A similar effect is seen in liver disease due to reduced gluconeogenesis and altered insulin metabolism. There is no fixed dose reduction formula; instead, doses should be titrated based on frequent blood glucose monitoring, with extra caution to avoid severe hypoglycaemia. In advanced kidney disease, insulin requirements may fluctuate significantly with each dialysis session.
Missed Dose
If you forget to inject your Protaphane dose, measure your blood glucose as soon as you remember. Depending on the timing and your blood glucose reading, you may take a reduced dose or wait until the next scheduled injection. Never take a double dose to compensate for a missed injection. Prolonged omission of insulin – especially in type 1 diabetes – can rapidly lead to hyperglycaemia and diabetic ketoacidosis (DKA), a medical emergency. Always contact your diabetes care team for advice if you are unsure how to manage a missed dose, and if you feel unwell, test for urine or blood ketones.
Overdose
An overdose of Protaphane causes hypoglycaemia, which can range from mild to severe. Because NPH insulin has a peak effect between 4 and 12 hours, hypoglycaemia from an overdose can be delayed and prolonged, sometimes requiring several hours of close monitoring or even hospital admission. Mild hypoglycaemia: Consume 15–20 grams of fast-acting carbohydrates (glucose tablets, fruit juice, regular fizzy drink) and recheck blood glucose after 15 minutes. Repeat if still below 4.0 mmol/L (70 mg/dL). Severe hypoglycaemia (unconsciousness, seizure, inability to swallow): Do not attempt to give food or drink by mouth. Administer glucagon (1 mg intramuscularly or subcutaneously, or nasal glucagon 3 mg) if available, and call emergency services immediately. Intravenous glucose may be required in a hospital setting. After recovery, the patient should eat a carbohydrate-rich snack or meal to prevent recurrence, and the insulin regimen should be reviewed to identify the cause.
What Are the Side Effects of Protaphane FlexPen?
Like all medicines, Protaphane FlexPen can cause side effects, although not everyone experiences them. The frequency and severity of side effects depend on the insulin dose, blood glucose control, injection technique and individual patient factors. Hypoglycaemia is by far the most common adverse reaction and can occur if the insulin dose is too high relative to the patient’s insulin requirement, if meals are missed or delayed, or if physical activity is greater than usual.
The following side effects have been reported with Protaphane and other human NPH insulin preparations, categorised by frequency according to international pharmacovigilance standards (CIOMS / EMA):
Very Common
- Hypoglycaemia (low blood sugar) – symptoms include sweating, trembling, hunger, palpitations, blurred vision, confusion, drowsiness, and in severe cases loss of consciousness or seizures
Common
- Injection site reactions – redness, swelling, itching, pain, or bruising at the injection site, usually mild and self-limiting
- Weight gain – a known effect of insulin therapy caused by the anabolic effect of insulin and reduced glycosuria (loss of glucose in urine)
Uncommon
- Lipodystrophy – localised thickening (lipohypertrophy) or thinning (lipoatrophy) of fat tissue at injection sites, caused by repeated injection in the same area
- Oedema – fluid retention, particularly at the start of insulin therapy or after a significant improvement in blood glucose control (“insulin oedema”)
- Visual disturbances – temporary changes in vision, usually at the start of treatment, caused by changes in lens refraction as blood glucose normalises; usually transient and resolves without treatment
Rare
- Peripheral neuropathy – painful neuropathy may occasionally occur with rapid improvement of blood glucose control (“treatment-induced neuropathy of diabetes”); usually temporary
- Generalised allergic reactions – urticaria (hives), rash, pruritus, or anaphylactic reactions (very rare; symptoms may include widespread skin rash, itching, swelling of face/lips/tongue, difficulty breathing, rapid heartbeat and drop in blood pressure)
- Diabetic retinopathy progression – rapid improvement in blood glucose control may be associated with temporary worsening of retinopathy; long-term control is protective
Very Rare / Unknown Frequency
- Cutaneous amyloidosis – a skin condition caused by repeated insulin injection at the same site, leading to lumps under the skin that can affect insulin absorption
- Insulin antibody formation – development of antibodies to human insulin, which rarely has clinical significance with modern human insulin preparations
- Anaphylactic shock – severe, life-threatening whole-body allergic reaction requiring immediate emergency treatment
If you experience any troublesome or persistent side effects, or any symptoms that concern you, contact your healthcare provider. Serious side effects such as severe hypoglycaemia or signs of an allergic reaction require immediate medical attention. In most countries, suspected adverse drug reactions can be reported through the national pharmacovigilance system (for example, the Yellow Card scheme in the UK, FDA MedWatch in the US, or the national authority in your country).
Lipodystrophy is preventable. Always rotate your injection sites within the same body region, using a different spot for each injection. Avoid injecting into lumps, hardened areas or areas with visible skin changes. Using a new needle for each injection also helps reduce the risk. If you notice any lumps or indentations at injection sites, inform your diabetes care team, as injecting into affected areas can lead to erratic insulin absorption and unstable blood glucose.
How Should You Store Protaphane FlexPen?
Correct storage of insulin is essential to maintain its effectiveness and safety. Improperly stored insulin may lose potency, leading to poor blood glucose control and unpredictable effects. The following storage guidelines apply to the Protaphane FlexPen:
- Before opening (not in use): Store in the refrigerator at 2–8°C (36–46°F). Keep away from the freezer compartment, cooling element and back wall of the refrigerator to avoid accidental freezing. Do not freeze insulin, and do not use a FlexPen that has been frozen – freezing destroys the insulin crystals and alters the product irreversibly.
- After opening (in use): A Protaphane FlexPen that is currently being used can be kept at room temperature (below 30°C / 86°F) for up to 6 weeks (42 days) and must then be discarded even if it still contains insulin. Once kept at room temperature, do not return the pen to the refrigerator.
- Protect from light and heat: Keep insulin away from direct sunlight, radiators and other heat sources. Never leave insulin in a car, especially during hot weather, or in checked luggage during air travel (cargo holds can reach freezing temperatures at altitude).
- Pen-cap and needle handling: Always keep the pen cap on the FlexPen when not in use to protect the contents from light. Never store the FlexPen with the needle attached, as this can allow air to enter the cartridge, cause insulin to leak out, and compromise sterility.
- Appearance check: Before each injection, inspect the Protaphane suspension after resuspension. It should appear uniformly white and cloudy. Do not use if it remains clear, contains visible clumps, flakes or particles that persist after gentle mixing, or if it appears frosted or discoloured.
- Expiry date: Do not use Protaphane FlexPen after the expiry date printed on the label and carton. The expiry date refers to the last day of the stated month. Unopened pens must also be discarded if they have passed their expiry date, even if they still appear normal.
- Disposal: Used FlexPens and needles must be disposed of safely. Needles should always be placed in a puncture-proof sharps container. Ask your pharmacist or local authority about safe disposal of used pens and unused medicines in accordance with local regulations.
When travelling, carry your insulin in your hand luggage – never in checked bags – in an insulated case or cool bag. Do not place insulin directly against ice packs, as direct contact with ice can freeze and destroy the product. In hot climates, use a specialised insulin cooling wallet. Always carry a letter from your healthcare provider confirming your need for insulin and injection supplies, particularly when flying internationally. Pack spare pens in case of loss or damage, and be aware of time-zone changes when planning your doses.
What Does Protaphane FlexPen Contain?
Each millilitre of Protaphane FlexPen 100 IU/ml contains 100 international units (equivalent to 3.5 mg) of human insulin. Each pen contains 3 ml of suspension, delivering a total of 300 IU. The insulin is produced using recombinant DNA technology, with Saccharomyces cerevisiae (baker’s yeast) as the host organism. This means no animal-derived insulin is used, making it suitable for patients who prefer biosynthetic human insulin for religious, ethical or medical reasons.
The complete list of excipients (inactive ingredients) in Protaphane FlexPen includes:
- Protamine sulphate: Forms the crystalline complex with insulin that produces the intermediate-acting absorption profile. Protamine is derived from fish (traditionally salmon) sperm. Patients with known fish allergy should discuss this with their healthcare provider, although clinically significant allergic reactions to protamine in insulin preparations are very rare.
- Zinc chloride: Stabilises the insulin-protamine crystals and supports the hexameric structure of insulin in suspension.
- Glycerol: Used as a tonicity agent to make the suspension isotonic with body tissues.
- Metacresol and phenol: Act as preservatives to prevent microbial growth in the multi-dose pen.
- Disodium phosphate dihydrate: A buffering agent that helps maintain the pH of the suspension.
- Sodium hydroxide and hydrochloric acid: Used for pH adjustment during manufacture.
- Water for injection: The solvent in which all other components are suspended.
The FlexPen device itself is a pre-filled, single-patient, multi-dose disposable injection pen constructed from plastic, with an internal glass cartridge containing the insulin. The pen is compatible with NovoFine and NovoTwist needles (sold separately).
Other presentations of the same insulin (same active substance, same concentration) are available from the manufacturer:
- Protaphane Penfill: 3 ml replaceable cartridges containing 100 IU/ml, for use in compatible Novo Nordisk durable insulin pens (e.g. NovoPen 4, NovoPen 5).
- Protaphane InnoLet: A pre-filled pen specifically designed for patients with visual or dexterity impairment, featuring a large dose display and extra-audible clicks.
- Protaphane vials: 10 ml vials containing 100 IU/ml (1,000 IU total), for use with insulin syringes. This presentation allows mixing with short-acting or rapid-acting insulin in the same syringe, which the pre-filled FlexPen does not.
The marketing authorisation holder for Protaphane is Novo Nordisk A/S, Bagsværd, Denmark. Novo Nordisk has manufactured insulin since 1923 and is one of the world’s largest producers of insulin products, alongside Eli Lilly and Sanofi.
How Should You Inject Protaphane FlexPen?
Proper injection technique is essential for consistent insulin delivery and optimal blood glucose control. Protaphane is a suspension (not a clear solution) and requires gentle mixing before each use. Follow these steps for correct injection:
- Wash your hands thoroughly with soap and water before handling your FlexPen.
- Check the pen: Confirm that you have the correct insulin (Protaphane FlexPen) by reading the label. Make sure the pen has not expired.
- Resuspend the insulin: Gently roll the pen between your palms 10 times and then invert it (turn upside down and back) at least 10 more times – giving a total of at least 20 mixing movements. The insulin should appear uniformly milky-white and cloudy. Do not shake vigorously, as this can cause frothing, air bubbles and inaccurate dosing.
- Inspect the insulin: After resuspension, look at the liquid. Do not use it if it remains clear, contains visible clumps or particles, or appears discoloured, frosted or damaged.
- Attach a new needle: Use a new NovoFine or NovoTwist needle for each injection. Pull off the paper tab, screw or push on the needle straight, and remove both the outer and inner needle caps.
- Perform an air shot (priming dose): Dial 2 units, hold the pen with the needle pointing upwards, and tap the cartridge gently to move any air bubbles to the top. Press the injection button fully until a drop of insulin appears at the needle tip. Repeat if no drop appears. This step ensures the pen and needle are working correctly.
- Dial your dose: Turn the dose selector to your prescribed number of units. If you dial past your dose, simply turn the selector back – no insulin is lost.
- Choose an injection site: Protaphane can be injected into the thigh, the abdominal wall (at least 5 cm from the navel), the upper outer arm (deltoid region) or the buttock (gluteal region). The rate of absorption may vary by site – generally fastest from the abdomen and slowest from the thigh or buttock. For consistency, many clinicians recommend using the same body region at the same time of day (e.g. always thigh at bedtime).
- Inject: Pinch a fold of skin (unless using a very short 4–5 mm needle) and insert the needle at a 90-degree angle. Press the injection button fully and hold the pen in place for at least 6 seconds before withdrawing the needle, to ensure the full dose is delivered. You may feel a slight click when the injection is complete.
- Dispose of the needle: Unscrew the needle immediately after injection and place it in a sharps container. Never reuse needles – reuse causes pain, bent tips, and increased risk of infection and lipohypertrophy.
- Replace the pen cap: Put the cap back on the FlexPen for storage.
Rotate your injection site within the same body region with each injection to reduce the risk of lipodystrophy and cutaneous amyloidosis. For example, if you inject into your left thigh at bedtime, move to a different spot on your left thigh (at least 1–2 cm apart) at the next injection. Regularly check your injection sites for lumps, indentations or skin changes, and report any abnormalities to your diabetes team. Many diabetes services use a simple “grid” approach where the patient mentally divides each injection region into small squares and uses each square in sequence.
Modern insulin needles are short (typically 4, 5, 6 or 8 mm). For most adults and children, 4 mm needles inserted at 90 degrees without pinching a skin fold are recommended, as they reliably deliver insulin into subcutaneous tissue while minimising the risk of intramuscular injection (which causes faster, less predictable absorption and higher hypoglycaemia risk). Longer needles may still be appropriate in specific situations – discuss this with your diabetes nurse.
Frequently Asked Questions About Protaphane FlexPen
Protaphane (NPH insulin) is an intermediate-acting human insulin with a pronounced peak effect between 4 and 12 hours after injection and a duration of up to 24 hours. Long-acting insulin analogues such as insulin glargine (Lantus, Toujeo) and insulin detemir (Levemir) have a flatter, more prolonged action profile with less peak effect, resulting in a lower risk of nocturnal hypoglycaemia in many patients. However, Protaphane remains widely used worldwide, is less expensive, and is effective for many patients. The choice between NPH insulin and long-acting analogues depends on individual patient factors, glycaemic targets, hypoglycaemia risk, cost and availability. International guidelines (ADA, NICE) recommend considering long-acting analogues particularly for patients with recurrent nocturnal hypoglycaemia or hypoglycaemia unawareness.
No. The FlexPen is a pre-filled, sealed device and must not be opened, refilled, or used to mix different insulins. If your treatment plan requires mixing NPH insulin with rapid-acting or short-acting insulin in the same syringe, your doctor can prescribe a vial-and-syringe form of Protaphane (or Insulatard) instead, or a pre-mixed insulin product such as Mixtard or NovoMix. When mixing NPH insulin with a rapid-acting or short-acting insulin from vials, always draw the clear (rapid- or short-acting) insulin into the syringe first, then the cloudy (NPH) insulin – this prevents contamination of the rapid-acting insulin vial with protamine.
Weight gain is a common side effect of insulin therapy, including Protaphane. Insulin promotes glucose uptake into cells and reduces the loss of glucose through the urine, which can lead to increased calorie retention. Additionally, patients who have had poorly controlled diabetes often gain weight as their blood glucose improves because calories that were previously lost in the urine are now being stored. To minimise weight gain, your healthcare team may advise dietary adjustments, regular physical activity and careful dose titration. In type 2 diabetes, combining insulin with metformin (weight-neutral) or a GLP-1 receptor agonist (which can promote weight loss) can help offset insulin-related weight gain.
After gently rolling and inverting the FlexPen at least 20 times, Protaphane should appear uniformly white and cloudy. If the suspension remains clear, or if you can see white clumps, particles, flakes, or a frosted appearance that does not disappear after gentle mixing, do not use that pen. These changes indicate that the insulin has been damaged – most often by freezing, excessive heat or vigorous shaking – and may not work correctly. Dispose of the damaged pen in a sharps container and use a new one. Always store insulin according to the recommended guidelines to prevent damage, and never leave a pen in a car, near a radiator or in direct sunlight.
Yes, Protaphane FlexPen is considered safe during pregnancy. Human insulin does not cross the placenta and does not cause harm to the developing baby. Maintaining good blood glucose control during pregnancy is essential, as uncontrolled diabetes increases the risk of birth defects, macrosomia (large baby), pre-eclampsia and neonatal complications. Insulin requirements change throughout pregnancy: they typically decrease in the first trimester, increase during the second and third trimesters, and drop rapidly after delivery. Pregnant women with diabetes should have frequent blood glucose monitoring and close contact with their diabetes care team. NPH insulin has extensive clinical experience and a long safety track record in pregnancy.
Alcohol can have unpredictable effects on blood glucose and insulin therapy. Moderate amounts of alcohol may initially raise blood sugar (particularly if the drinks contain carbohydrates), but alcohol also inhibits hepatic gluconeogenesis – the liver’s ability to produce glucose – which can cause delayed and prolonged hypoglycaemia that may occur several hours after drinking, even overnight. This risk is especially high if alcohol is consumed without food or after exercise. If you choose to drink alcohol, do so in moderation, always with food, and monitor your blood glucose more frequently. Never substitute alcohol for a meal, and be aware that others may mistake symptoms of hypoglycaemia for intoxication.
Once a Protaphane FlexPen has been taken into use (first injection given), it can be kept at room temperature below 30°C (86°F) for up to 6 weeks (42 days), after which it should be discarded even if it still contains insulin. Write the date of first use on the pen or its carton so you remember when to discard it. Do not store the pen in the refrigerator once it is in use, and do not expose it to direct sunlight, heat or freezing temperatures. Always perform an appearance check before each injection.
References
This article is based on the following international medical guidelines and peer-reviewed sources:
- European Medicines Agency (EMA). Protaphane – Summary of Product Characteristics. Last updated 2024. Available at: www.ema.europa.eu
- World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd List (2023). Geneva: WHO; 2023.
- American Diabetes Association (ADA). Standards of Care in Diabetes – 2024. Diabetes Care. 2024;47(Suppl 1):S1–S321.
- International Diabetes Federation (IDF). IDF Diabetes Atlas, 10th Edition. Brussels: IDF; 2021. Available at: diabetesatlas.org
- National Institute for Health and Care Excellence (NICE). Type 1 diabetes in adults: diagnosis and management (NG17). Updated 2022. Available at: www.nice.org.uk/guidance/ng17
- National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management (NG28). Updated 2022. Available at: www.nice.org.uk/guidance/ng28
- British National Formulary (BNF). Insulin isophane human. Joint Formulary Committee. London: BMJ Publishing Group and Pharmaceutical Press; 2024.
- Holman RR, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357(17):1716–1730. doi: 10.1056/NEJMoa075392
- Heller S, et al. Hypoglycaemia in patients with type 2 diabetes treated with insulin: it can happen. BMJ Open Diabetes Res Care. 2020;8(1):e001194.
- Blumer I, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227–4249.
- Frid AH, et al. New insulin delivery recommendations. Mayo Clin Proc. 2016;91(9):1231–1255.
- Novo Nordisk. Protaphane / Insulatard – Prescribing Information / Patient Information Leaflet. Bagsværd, Denmark.
Editorial Team
This article has been researched, written, and medically reviewed by the iMedic Medical Editorial Team, which includes licensed specialists in endocrinology, diabetology and clinical pharmacology.
Content researched and written by medical professionals with expertise in diabetes care and pharmacology. Based on current international guidelines (ADA, EMA, NICE, WHO) and peer-reviewed literature.
All medical claims reviewed by the iMedic Medical Review Board. Evidence level: Grade 1A based on systematic reviews of randomised controlled trials and authoritative international guidelines.
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