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Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should consider the use of adequate contraception to prevent pregnancy and continue its use for at least five months after the last Humira treatment.
Pregnancy
A large number (approximately 2100) of prospectively collected pregnancies exposed to adalimumab resulting in live birth with known outcomes, including more than 1500 exposed during the first trimester, does not indicate an increase in the rate of malformation in the newborn.
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn's disease (CD) treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects. The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69 (8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA (unadjusted OR 1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD combined. There were no distinct differences between adalimumab-treated and untreated women for the secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and serious or opportunistic infections and no stillbirths or malignancies were reported. The interpretation of data may be impacted due to methodological limitations of the study, including small sample size and non-randomized design.
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available (see section 5.3).
Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal immune responses in the newborn. Adalimumab should only be used during pregnancy if clearly needed.
Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.
Breast-feeding
Limited information from the published literature indicates that adalimumab is excreted in breast milk at very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No effects on the breastfed newborns/infants are anticipated. Consequently, Humira can be used during breastfeeding.
Fertility
Preclinical data on fertility effects of adalimumab are not available.
4.7 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Humira may have a minor influence on the ability to drive and use machines. Vertigo and visual impairment may occur following administration of Humira (see section 4.8).
4.8 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
Humira was studied in 9,506 patients in pivotal controlled and open label trials for up to 60 months or more. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of AS), psoriatic arthritis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients receiving Humira and 3,801 patients receiving placebo or active comparator during the controlled period.
The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies was 5.9% for patients taking Humira and 5.4% for control treated patients.
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for Humira. TNF-antagonists, such as Humira affect the immune system and their use may affect the body's defence against infection and cancer.
Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been reported with use of Humira.
Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.
Paediatric population
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.
Tabulated list of adverse reactions
The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 4 below: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency seen among the various indications has been included. An asterisk (*) appears in the SOC column if further information is found elsewhere in sections 4.3, 4.4 and 4.8.
Table 4
Undesirable Effects
System Organ Class
Frequency
Adverse Reaction
Infections and infestations*
Very common
Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral)
Common
Systemic infections (including sepsis, candidiasis and influenza), intestinal infections (including gastroenteritis viral), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), ear infections, oral infections (including herpes simplex, oral herpes and tooth infections), reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, joint infections
Uncommon
Neurological infections (including viral meningitis), opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and mycobacterium avium complex infection), bacterial infections, eye infections, diverticulitis1)
Neoplasms benign, malignant and unspecified (including cysts and polyps)*
Common
Skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma), benign neoplasm
Uncommon
Lymphoma**, solid organ neoplasm (including breast cancer, lung neoplasm and thyroid neoplasm), melanoma**
Rare
Leukaemia1)
Not known
Hepatosplenic T-cell lymphoma1) Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1) Kaposi's sarcoma
Blood and the lymphatic system disorders*
Very common
Leukopenia (including neutropenia and agranulocytosis), anaemia
Common
Leucocytosis, thrombocytopenia
Uncommon
Idiopathic thrombocytopenic purpura
Rare
Pancytopenia
Immune system disorders*
Common
Hypersensitivity, allergies (including seasonal allergy)
Uncommon
Sarcoidosis1), vasculitis
Rare
Anaphylaxis1)
Metabolism and nutrition disorders
Very common
Lipids increased
Common
Hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemia, dehydration
Psychiatric disorders
Common
Mood alterations (including depression), anxiety, insomnia
Nervous system disorders*
Very common
Headache
Common
Paraesthesias (including hypoesthesia), migraine, nerve root compression
Uncommon
Cerebrovascular accident1), tremor, neuropathy
Rare
Multiple sclerosis, demyelinating disorders (e.g. optic neuritis, Guillain-Barré syndrome) 1)
Eye disorders
Common
Visual impairment, conjunctivitis, blepharitis, eye swelling
Uncommon
Diplopia
Ear and labyrinth disorders
Common
Vertigo
Uncommon
Deafness, tinnitus
Cardiac disorders*
Common
Tachycardia
Uncommon
Myocardial infarction1), arrhythmia, congestive heart failure
Rare
Cardiac arrest
Vascular disorders
Common
Hypertension, flushing, haematoma
Uncommon
Aortic aneurysm, vascular arterial occlusion, thrombophlebitis
Respiratory, thoracic and mediastinal disorders*
Common
Asthma, dyspnoea, cough
Uncommon
Pulmonary embolism1), interstitial lung disease, chronic obstructive pulmonary disease, pneumonitis, pleural effusion1)
Rare
Pulmonary fibrosis1)
Gastrointestinal disorders
Very common
Abdominal pain, nausea and vomiting
Common
GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome
Uncommon
Pancreatitis, dysphagia, face oedema
Rare
Intestinal perforation1)
Hepato-biliary disorders*
Very Common
Elevated liver enzymes
Uncommon
Cholecystitis and cholelithiasis, hepatic steatosis, bilirubin increased
Rare
Hepatitis reactivation of hepatitis B1)
autoimmune hepatitis1)
Not known
Liver failure1)
Skin and subcutaneous tissue disorders
Very Common
Rash (including exfoliative rash)
Common
Worsening or new onset of psoriasis (including palmoplantar pustular psoriasis)1), urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia1), pruritus
Uncommon
Night sweats, scar
Rare
Erythema multiforme1), Stevens-Johnson syndrome1), angioedema1), cutaneous vasculitis1) lichenoid skin reaction1)
Not known
Worsening of symptoms of dermatomyositis1)
Musculoskeletal and connective tissue disorders
Very common
Musculoskeletal pain
Common
Muscle spasms (including blood creatine phosphokinase increased)
Uncommon
Rhabdomyolysis, systemic lupus erythematosus
Rare
Lupus-like syndrome1)
Renal and urinary disorders
Common
Renal impairment, haematuria
Uncommon
Nocturia
Reproductive system and breast disorders
Uncommon
Erectile dysfunction
General disorders and administration site conditions*
Very Common
Injection site reaction (including injection site erythema)
Common
Chest pain, oedema, pyrexia1)
Uncommon
Inflammation
Investigations*
Common
Coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased
Not known
Weight Increased2)
Injury, poisoning and procedural complications
Common
Impaired healing
* further information is found elsewhere in sections 4.3, 4.4 and 4.8
** including open label extension studies
1) including spontaneous reporting data
2) The mean weight change from baseline for adalimumab ranged from 0.3 kg to 1.0 kg across adult indications compared to (minus) -0.4 kg to 0.4 kg for placebo over a treatment period of 4-6 months. Weight increase of 5-6 kg has also been observed in long-term extension studies with mean exposures of approximately 1-2 years without control group, particularly in patients with Crohn's disease and Ulcerative colitis. The mechanism behind this effect is unclear but could be associated with the anti inflammatory effect of adalimumab.
Hidradenitis suppurativa
The safety profile for patients with HS treated with Humira weekly was consistent with the known safety profile of Humira.
Uveitis
The safety profile for patients with uveitis treated with Humira every other week was consistent with the known safety profile of Humira.
Description of selected adverse reactions
Injection site reactions
In the pivotal controlled trials in adults and children, 12.9% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.2% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.
Infections
In the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the Humira treated patients and 1.46 per patient year in the placebo and active control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on Humira after the infection resolved.
The incidence of serious infections was 0.04 per patient year in Humira treated patients and 0.03 per patient year in placebo and active control − treated patients.
In controlled and open label adult and paediatric studies with Humira, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.
Malignancies and lymphoproliferative disorders
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient years during Humira trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric patients with an exposure of 498.1 patient years during Humira trials in paediatric patients with Crohn's disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during a Humira trial in paediatric patients with chronic plaque psoriasis. No malignancies were observed in 93 paediatric patients with an exposure of 65.3 patient years during a Humira trial in paediatric patients with ulcerative colitis. No malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a Humira trial in paediatric patients with uveitis.
During the controlled portions of pivotal Humira trials in adults of at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn's disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per 1,000 patient-years among 5,291 Humira treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 patient-years among 3,444 control patients (median duration of treatment was 4.0 months for Humira and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among Humira-treated patients and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among Humira-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.
When combining controlled portions of these trials and ongoing and completed open label extension studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years.
In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and 0.3 per 1,000 patient treatment years, respectively (see section 4.4).
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see section 4.4).
Autoantibodies
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I − V. In these trials, 11.9% of patients treated with Humira and 8.1% of placebo and active control − treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at Week 24. Two patients out of 3,441 treated with Humira in all rheumatoid arthritis and psoriatic arthritis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.
Hepato-biliary events
In controlled Phase 3 trials of Humira in patients with rheumatoid arthritis and psoriatic arthritis with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of Humira-treated patients and 1.6% of control-treated patients.
In controlled Phase 3 trials of Humira in patients with polyarticular juvenile idiopathic arthritis who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x ULN occurred in 6.1% of Humira-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of Humira in patients with polyarticular juvenile idiopathic arthritis who were 2 to < 4 years.
In controlled Phase 3 trials of Humira in patients with Crohn's disease and ulcerative colitis with a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of Humira-treated patients and 0.9% of controlled-treated patients.
In the Phase 3 trial of Humira in patients with paediatric Crohn's disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.
In controlled Phase 3 trials of Humira in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of Humira-treated patients and 1.8% of control-treated patients.
No ALT elevations ≥ 3 X ULN occurred in the Phase 3 trial of Humira in paediatric patients with plaque psoriasis.
In controlled trials of Humira (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of Humira-treated patients and 0.6% of control-treated patients.
In controlled trials of Humira (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5 days and 105.0 days in Humira-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of Humira-treated patients and 2.4% of control-treated patients.
In the controlled Phase 3 trial of Humira in patients with paediatric ulcerative colitis (N=93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every Week (N=32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of patients.
Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have also been post-marketing reports of liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.
Concurrent treatment with azathioprine/6-mercaptopurine
In adult Crohn's disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of Humira and azathioprine/6-mercaptopurine compared with Humira alone.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Clinical particulars - Overdose | Overdose
No dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has been multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended dose.
5. Pharmacological properties
5.1 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption and distribution
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/ml (without concomitant methotrexate) and 8 to 9 μg/ml (with concomitant methotrexate), respectively. The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.
In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/ml during adalimumab 40 mg every other week monotherapy treatment.
In adult patients with hidradenitis suppurativa, a dose of 160 mg Humira on Week 0 followed by 80 mg on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/ml at Week 2 and Week 4. The mean steady-state trough concentration at Week 12 through Week 36 were approximately 8 to 10 μg/ml during adalimumab 40 mg every week treatment.
Adalimumab exposure in adolescent HS patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn's disease, and enthesitis-related arthritis). The recommended adolescent HS dosing schedule is 40 mg every other week. Since exposure to adalimumab can be affected by body size, adolescents with higher body weight and inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.
In patients with Crohn's disease, the loading dose of 80 mg Humira on Week 0 followed by 40 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 7 μg/ml were observed in Crohn's disease patients who received a maintenance dose of 40 mg Humira every other week.
In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At Week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7 ± 6.6 μg/ml for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 μg/ml for patients < 40 kg (80/40 mg).
For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough concentrations at Week 52 were 9.5 ± 5.6 μg/ml for the Standard Dose group and 3.5 ± 2.2 μg/ml for the Low Dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment eow for 52 weeks. For patients who dose escalated from eow to weekly regimen, the mean (±SD) serum concentrations of adalimumab at Week 52 were 15.3 ± 11.4 μg/ml (40/20 mg, weekly) and 6.7 ± 3.5 μg/ml (20/10 mg, weekly).
In patients with ulcerative colitis, a loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/ml during the induction period. Mean steady-state trough levels of approximately 8 μg/ml were observed in ulcerative colitis patients who received a maintenance dose of 40 mg Humira every other week.
Following the subcutaneous administration of body weight-based dosing of 0.6 mg/kg (maximum of 40 mg) every other week to paediatric patients with ulcerative colitis, the mean trough steady-state serum adalimumab concentration was 5.01±3.28 µg/ml at Week 52. For patients who received 0.6 mg/kg (maximum of 40 mg) every week, the mean (±SD) trough steady-state serum adalimumab concentration was 15.7±5.60 μg/ml at Week 52.
In adult patients with uveitis, a loading dose of 80 mg adalimumab on Week 0 followed by 40 mg adalimumab every other week starting at Week 1, resulted in mean steady-state concentrations of approximately 8 to 10 μg/ml.
Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn's disease, and enthesitis-related arthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years. The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic exposure.
Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients with adolescent HS, and paediatric patients ≥ 40 kg with CD and UC).
Exposure-response relationship in paediatric population
On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposure-response relationship was established between plasma concentrations and PedACR 50 response. The apparent adalimumab plasma concentration that produces half the maximum probability of PedACR 50 response (EC50) was 3 μg/ml (95% CI: 1-6 μg/ml).
Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a similar apparent EC50 of approximately 4.5 μg/ml (95% CI 0.4-47.6 and 1.9-10.5, respectively).
Elimination
Population pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA.
Hepatic or renal impairment
Humira has not been studied in patients with hepatic or renal impairment.
5.3 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity, repeated dose toxicity, and genotoxicity.
An embryo-foetal developmental toxicity/perinatal developmental study has been performed in cynomolgus monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of fertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate models for an antibody with limited cross-reactivity to rodent TNF and to the development of neutralising antibodies in rodents.
6. |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - List of excipients | List of excipients
Mannitol
Polysorbate 80
Water for injections
6.2 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - Incompatibilities | Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled syringe or pre-filled pen in its outer carton in order to protect from light.
A single Humira pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of 25°C for a period of up to 14 days. The syringe or pen must be protected from light and discarded if not used within the 14-day period.
6.5 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Humira 80 mg solution for injection in pre-filled syringe
Humira 80 mg solution for injection in single-use pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and a needle with a needle shield (thermoplastic elastomer).
Packs of:
• 1 pre-filled syringe (0.8 ml sterile solution) with 1 alcohol pad in a blister.
Humira 80 mg solution for injection in pre-filled pen
Humira 80 mg solution for injection in single-use pre-filled pen for patient use containing a pre-filled syringe. The syringe inside the pen is made from type 1 glass with a plunger stopper (bromobutyl rubber) and a needle with a needle shield (thermoplastic elastomer).
Packs of:
• 1 pre-filled pen (0.8 ml sterile solution), with 2 alcohol pads in a blister.
• 3 pre-filled pens (0.8 ml sterile solution), with 4 alcohol pads in a blister.
Not all presentations or pack sizes may be marketed.
6.6 |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Marketing authorisation holder | AbbVie Ltd
Maidenhead
Berkshire
SL6 4UB
UK
8. Marketing authorisation number(s)
PLGB 41042/0026
9. |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 08 September 2003
Date of latest renewal: 08 September 2008
10. |
Humira 80 mg/0.8 ml solution for injection in pre-filled syringe | Date of revision of the text | 01 April 2021 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Name of the medicinal product | Humulin® I (Isophane) 100 IU/ml suspension for injection in cartridge.
2. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Qualitative and quantitative composition | 1 ml contains 100 IU insulin human (produced in E. coli by recombinant DNA technology).
One cartridge contains 3 ml equivalent to 300 IU of isophane insulin.
For a full list of excipients, see section 6.1.
3. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical form | A suspension for injection in a cartridge.
Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.
4. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.
4.2 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage should be determined by the physician, according to the requirement of the patient.
Paediatric population
No data are available
Method of administration
Humulin I in cartridges is only suitable for subcutaneous injections from a reusable pen. This formulation should not be administered intravenously.
Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
4.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Contraindications | Contraindications
Hypoglycaemia.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, unless used as part of a desensitisation programme.
Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.
4.4 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.
Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and hyperglycaemic reactions can cause loss of consciousness, coma or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.
Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.
Combination of human insulin with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and human insulin is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.
Instructions for use and handling
To prevent the possible transmission of disease, each cartridge must be used by one patient only, even if the needle on the delivery device is changed.
Pens to be used with Humulin I cartridges
The cartridges should only be used in conjunction with a Lilly reusable insulin pen and should not be used with any other reusable pen as the dosing accuracy has not been established with other pens.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.
4.5 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.
Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.
Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.
Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.
4.6 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
It is essential to maintain good control of the insulin treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctors if they are pregnant or are contemplating pregnancy.
Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes.
Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.
4.7 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving; this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Undesirable effects | Undesirable effects
Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise.
Local allergy in patients is common (≥1/100 to <1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic allergy, which is very rare (<1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required.
Lipodystrophy at the injection site is uncommon (≥1/1,000 to <1/100).
Skin and subcutaneous tissue disorders: Frequency “unknown”: Cutaneous amyloidosis
Skin and subcutaneous tissue disorders:
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (See section 4.4).
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Clinical particulars - Overdose | Overdose
Insulin has no specific overdose definitions, because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or sugar products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously, if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may occur after apparent clinical recovery.
5. Pharmacological properties
5.1 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.
5.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.
6. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - List of excipients | List of excipients
m-cresol
glycerol
phenol
protamine sulfate
dibasic sodium phosphate 7H2O
zinc oxide
water for injections.
The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.
6.2 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.
6.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Shelf life | Shelf life
Unused cartridge
3 years.
After cartridge insertion
28 days.
6.4 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Unused cartridge
Store in a refrigerator (2°C – 8°C). Do not freeze. Do not expose to excessive heat or direct sunlight.
After cartridge insertion
Store below 30°C. Do not refrigerate. The pen with the inserted cartridge should not be stored with the needle attached.
6.5 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber). Pack size of 5 or 10. Not all pack sizes may be marketed.
6.6 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Cartridges can be used until empty, then properly discard. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for use and handling
To prevent the possible transmission of disease, each cartridge must be used by one patient only, even if the needle on the delivery device is changed.
The cartridges should only be used in conjunction with a Lilly reusable insulin pen and should not be used with any other reusable pen as the dosing accuracy has not been established with other pens.
a) Preparing a dose
Cartridges containing Humulin I formulation should be rolled in the palms of the hands ten times and inverted 1800 ten times immediately before use to resuspend the insulin until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.
The cartridges should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance.
The cartridges are not designed to allow any other insulin to be mixed in the cartridge.
Cartridges are not designed to be refilled.
The manufacturer's instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection.
b) Injecting a dose
Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse.
Use of the injection sites should be rotated so that the same is not used more than approximately once a month.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
7. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Marketing authorisation holder | Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
8. Marketing authorisation number(s)
PL 14895/0296
9. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Date of first authorisation/renewal of the authorisation | 30 July 2019
10. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in cartridge | Date of revision of the text | 08 April 2021
LEGAL CATEGORY
POM
HU132 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Name of the medicinal product | Humulin® I (Isophane) 100 IU/ml suspension for injection in vial
2. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Qualitative and quantitative composition | 1 ml contains 100 IU insulin human (produced in E. coli by recombinant DNA technology).
One vial contains 10 ml equivalent to 1000 IU of isophane insulin.
For a full list of excipients, see section 6.1.
3. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical form | A suspension for injection in a vial.
Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.
4. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.
4.2 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage should be determined by the physician, according to the requirement of the patient.
Paediatric population
No data are available.
Method of administration
Humulin I should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously.
Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.
Humulin I (Isophane) may be administered in combination with Humulin S (Soluble). (See Instructions for use and handling for Mixing of Insulins).
Each pack contains a patient information leaflet with instructions on how to inject insulin.
4.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Contraindications | Contraindications
Hypoglycaemia.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, unless used as part of a desensitisation programme.
Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.
4.4 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.
Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and hyperglycaemic reactions can cause loss of consciousness, coma or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.
Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.
Combination of human insulin with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and human insulin is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.
4.5 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.
Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.
Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.
Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.
4.6 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
It is essential to maintain good control of the insulin treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctors if they are pregnant or are contemplating pregnancy.
Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes.
Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.
4.7 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Undesirable effects | Undesirable effects
Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise.
Local allergy in patients is common (≥ 1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required.
Lipodystrophy at the injection site is uncommon (≥ 1/1,000 to < 1/100).
Skin and subcutaneous tissue disorders: Frequency “unknown”: Cutaneous amyloidosis
Skin and subcutaneous tissue disorders:
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (See section 4.4).
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Clinical particulars - Overdose | Overdose
Insulin has no specific overdose definitions, because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or sugar products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously, if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may occur after apparent clinical recovery.
5. Pharmacological properties
5.1 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.
5.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.
6. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - List of excipients | List of excipients
m-cresol
glycerol
phenol
protamine sulfate
dibasic sodium phosphate 7H2O
zinc oxide
water for injections.
The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.
6.2 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.
6.3 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - Shelf life | Shelf life
Unopened vials
3 years.
After first use
28 days.
6.4 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not freeze. Do not expose to excessive heat or direct sunlight.
Unopened vials
Store in a refrigerator (2°C - 8°C).
After first use
Store below 30°C.
6.5 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
10 ml of suspension in a vial (type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic). Pack size 1 or 2 or 5 (5 x 1). Not all pack sizes may be marketed.
6.6 |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Do not reuse needles. Dispose of the needle in a responsible manner. Needles must not be shared. Vials can be used until empty, then properly discard. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for use and handling
A suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings).
a) Preparing a dose
Vials containing Humulin I formulation should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed.
Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.
The vials should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the vial, giving a frosted appearance.
Mixing of insulins: The shorter acting insulin should be drawn into the syringe first, to prevent contamination of the vial by the longer acting preparation. It is advisable to inject directly after mixing. However, if a delay is necessary, a consistent routine must be followed.
Alternatively a separate syringe or, separate cartridges of Humulin S and I, can be used for administration of the correct amount of each formulation.
Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse.
Use an insulin syringe marked for the strength of insulin being administered.
b) Injecting a dose
Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
7. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Marketing authorisation holder | Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
8. Marketing authorisation number(s)
PL 14895/0295
9. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Date of first authorisation/renewal of the authorisation | 30 July 2019
10. |
HUMULIN I (Isophane) 100IU/ml suspension for injection in vial | Date of revision of the text | 26 January 2021
LEGAL CATEGORY
POM
HU123M |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Name of the medicinal product | Humulin I KwikPen (Isophane) 100 IU/ml suspension for injection
2. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Qualitative and quantitative composition | 1 ml contains 100 IU insulin human (produced in E. coli by recombinant DNA technology).
One pre-filled pen contains 3 ml equivalent to 300 IU of isophane insulin.
For a full list of excipients, see section 6.1.
3. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical form | A suspension for injection in a pre-filled pen.
Humulin I is a sterile suspension of a white, crystalline precipitate of isophane human insulin in an isotonic phosphate buffer.
4. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.
4.2 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage should be determined by the physician, according to the requirement of the patient.
Paediatric population
No data are available.
Method of administration
Humulin I in pre-filled pen is only suitable for subcutaneous injections. This formulation should not be administered intravenously.
Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
4.3 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Contraindications | Contraindications
Hypoglycaemia.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, unless used as part of a desensitisation programme.
Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.
4.4 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.
Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and hyperglycaemic reactions can cause loss of consciousness, coma or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in insulin- dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.
Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.
Combination of human insulin with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and human insulin is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.
Instructions for use and handling
To prevent the possible transmission of disease, each pen must be used by one patient only, even if the needle is changed.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.
4.5 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.
Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.
Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.
Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.
4.6 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
It is essential to maintain good control of the insulin treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctors if they are pregnant or are contemplating pregnancy.
Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes.
Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.
4.7 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Undesirable effects | Undesirable effects
Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient's level of diet and exercise.
Local allergy in patients is common (≥ 1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required.
Lipodystrophy at the injection site is uncommon (≥ 1/1,000 to < 1/100).
Skin and subcutaneous tissue disorders: Frequency “unknown”: Cutaneous amyloidosis
Skin and subcutaneous tissue disorders:
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (See section 4.4).
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Clinical particulars - Overdose | Overdose
Insulin has no specific overdose definitions, because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or sugar products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously, if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may occur after apparent clinical recovery.
5. Pharmacological properties
5.1 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.
5.3 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.
6. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - List of excipients | List of excipients
m-cresol
glycerol
phenol
protamine sulfate
dibasic sodium phosphate 7H2O
zinc oxide
water for injections.
The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.
6.2 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.
6.3 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - Shelf life | Shelf life
Unused pre-filled pens
3 years.
After first use
28 days.
6.4 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Unused pre-filled pens
Store in a refrigerator (2°C – 8°C). Do not freeze. Do not expose to excessive heat or direct sunlight.
After first use
Store below 30°C. Do not refrigerate. The pre-filled pen should not be stored with the needle attached.
6.5 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
3 ml suspension in a cartridge (type I glass) with a plunger head at the bottom (rubber) and disc seal at the top (rubber) in a pre-filled pen. Pack size of 5, 6 or 10 (2 x 5). Not all pack sizes may be marketed.
6.6 |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Do not reuse needles. Dispose of the needle in a responsible manner. Needles and pens must not be shared. Humulin I KwikPen can be used until empty, then properly discard. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for use and handling
To prevent the possible transmission of disease, each pen must be used by one patient only, even if the needle is changed.
A suspension for injection in a pre-filled / disposable pen injector containing a 3ml cartridge. Humulin I KwikPen delivers up to 60 units per dose in single unit increments.
a) Preparing a dose
Humulin KwikPen containing Humulin I formulation should be rolled in the palms of the hands ten times and inverted 180° ten times immediately before use to resuspend the insulin until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed. Cartridges contain a small glass bead to assist mixing. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.
The pre-filled pen should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the cartridge, giving a frosted appearance.
The cartridges are not designed to allow any other insulin to be mixed in the cartridge. Cartridges are not designed to be refilled.
Follow the instructions with Humulin I KwikPen for attaching the needle and administering the insulin injection.
For Humulin I KwikPen, a needle must always be attached before priming, dialing and injecting an insulin dose. Humulin I KwikPen should always be primed before each injection. Failure to prime Humulin I KwikPen may result in an inaccurate dose.
b) Injecting a dose
Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse. Use of the injection sites should be rotated so that the same is not used more than approximately once a month.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
7. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Marketing authorisation holder | Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
8. Marketing authorisation number(s)
PL 14895/0297
9. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Date of first authorisation/renewal of the authorisation | 30 July 2019
10. |
HUMULIN I KwikPen (Isophane) 100IU/ml suspension for injection | Date of revision of the text | 26 January 2021
LEGAL CATEGORY
POM
HU128M |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Name of the medicinal product | Humulin® M3 (Mixture 3) 100 IU/ml suspension for injection in cartridge.
2. |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Qualitative and quantitative composition | 1 ml contains 100 IU insulin human (produced in E. coli by recombinant DNA technology).
One cartridge contains 3 ml equivalent to 300 IU of biphasic isophane insulin – 30 % soluble insulin / 70 % isophane insulin.
For a full list of excipients, see section 6.1.
3. |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Pharmaceutical form | A suspension for injection in a cartridge.
Humulin M3 is a sterile suspension of human insulin in the proportion of 30 % soluble insulin to 70 % isophane insulin.
4. |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.
4.2 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage should be determined by the physician, according to the requirement of the patient.
Paediatric population
No data are available
Method of administration
Humulin M3 in cartridges is only suitable for subcutaneous injections from a reusable pen. This formulation should not be administered intravenously.
Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.
Humulin Mixture formulation is a ready-made defined mixture of soluble and isophane insulin designed to avoid the need for the patient to mix insulin preparations. A patient's treatment regimen should be based on their individual metabolic requirements.
Each pack contains a patient information leaflet with instructions on how to inject insulin.
4.3 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Contraindications | Contraindications
Hypoglycaemia.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, unless used as part of a desensitisation programme.
Under no circumstances should any Humulin formulation other than Humulin S (Soluble) be given intravenously.
4.4 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.
Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.
A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and hyperglycaemic reactions can cause loss of consciousness, coma or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.
Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.
Combination of human insulin with pioglitazone
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and human insulin is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.
Instructions for use and handling
To prevent the possible transmission of disease, each cartridge must be used by one patient only, even if the needle on the delivery device is changed.
Pens to be used with Humulin M3 cartridges
The cartridges should only be used in conjunction with a Lilly reusable insulin pen and should not be used with any other reusable pen as the dosing accuracy has not been established with other pens.
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.
4.5 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.
Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.
Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.
Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.
4.6 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
It is essential to maintain good control of the insulin treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctors if they are pregnant or are contemplating pregnancy.
Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes.
Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.
4.7 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Undesirable effects | Undesirable effects
Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise.
Local allergy in patients is common (≥ 1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required.
Lipodystrophy at the injection site is uncommon (≥ 1/1,000 to < 1/100).
Skin and subcutaneous tissue disorders: Frequency “unknown”: Cutaneous amyloidosis
Skin and subcutaneous tissue disorders:
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (See section 4.4).
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Clinical particulars - Overdose | Overdose
Insulin has no specific overdose definitions, because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or sugar products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously, if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may occur after apparent clinical recovery.
5. Pharmacological properties
5.1 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.
5.3 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.
6. |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - List of excipients | List of excipients
m-cresol
glycerol
phenol
protamine sulfate
dibasic sodium phosphate 7H2O
zinc oxide
water for injections.
The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.
6.2 |
HUMULIN M3 (Mixture 3) 100IU/ml suspension for injection in cartridge | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.
6.3 |
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