medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
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Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Overdose | Overdose
There is no information available on overdose with the saxagliptin/dapagliflozin fixed dose combination. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.
Saxagliptin
Saxagliptin had no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). Saxagliptin and its major metabolite are removed by haemodialysis (23% of dose over four hours).
Dapagliflozin
Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function. The removal of dapagliflozin by haemodialysis has not been studied.
5. Pharmacological properties
5.1 |
Qtern 5 mg/10 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Saxagliptin/dapagliflozin combination: Overall, the pharmacokinetics of saxagliptin and dapagliflozin were not affected in clinically relevant manner when administered as a fixed dose combination compared with independent doses of saxagliptin and dapagliflozin.
The following reflects the pharmacokinetic properties of the saxagliptin/dapagliflozin fixed dose combination unless stated that the presented data are from administration of saxagliptin or dapagliflozin.
Bioequivalence has been confirmed between the Qtern 5 mg/10 mg tablet and the individual saxagliptin 5 mg and dapagliflozin 10 mg tablets after single dose administration in the fasted state in healthy subjects. The pharmacokinetics of dapagliflozin, and saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.
Administration of the saxagliptin/dapagliflozin fixed dose combination with a high-fat meal decreases dapagliflozin Cmax by up to 35% and prolongs Tmax by approximately 1.5 hours, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. There was no food effect observed for saxagliptin. This medicinal product can be administered with or without food.
Interactions with other medicinal products
Saxagliptin/dapagliflozin combination: No interaction studies have been performed with the saxagliptin/dapagliflozin fixed dose combination and other medicinal products. Such studies have been conducted with the individual active substances.
Saxagliptin: In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4.
Dapagliflozin: In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.
Absorption
Saxagliptin: Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng h/mL and 214 ng h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.
Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax and AUC values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Distribution
Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. The volume of distribution of saxagliptin was 205 L.
Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 L.
Biotransformation
Saxagliptin: The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major active metabolite of saxagliptin, 5-OH-saxagliptin, is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.
Dapagliflozin: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.
Elimination
Saxagliptin: The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion.
Dapagliflozin: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.
Linearity
Saxagliptin: The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
Dapagliflozin: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.
Special populations
Renal impairment
Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe renal impairment (or ESRD) classified on the basis of creatinine clearance the mean AUC values of saxagliptin were 1.2-, and up to 2.1- and 4.5- fold higher, respectively, than AUC values in subjects with normal renal function. The AUC values of 5-OH-saxagliptin were also increased. The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite.
Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known.
Hepatic impairment
Saxagliptin: In subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 (saxagliptin metabolite) were 22%, 7% and 33% lower, respectively, than those observed in healthy subjects.
Dapagliflozin: In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.
Elderly
Saxagliptin: Elderly patients (65–80 years) had about 60% higher saxagliptin AUC than young patients (18–40 years). This is not considered clinically meaningful, therefore, no dose adjustment for saxagliptin is recommended on the basis of age alone.
Dapagliflozin: There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients > 70 years old.
Gender
Saxagliptin: Females had approximately 25% higher systemic exposure values for saxagliptin. There were no clinically relevant differences observed in saxagliptin pharmacokinetics between males and females.
Dapagliflozin: The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males.
Race
Saxagliptin: Race was not identified as a statistically significant covariate on the apparent clearance of saxagliptin and its metabolite.
Dapagliflozin: There were no clinically relevant differences in systemic exposures between White, Black or Asian races.
Body weight
Saxagliptin: Body weight had a small and non-clinically meaningful impact on saxagliptin exposure. Females had approximately 25% higher systemic-exposure values for saxagliptin, this difference is considered not clinically relevant.
Dapagliflozin: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high-weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.
5.3 |
Qtern 5 mg/10 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical studies of either saxagliptin or dapagliflozin revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity or carcinogenicity.
Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) in cynomolgus monkeys. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose (RHD) of 5 mg/day. The clinical relevance of the skin lesions is not known and skin lesions have not been observed in humans.
Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD.
Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.
Reproductive and developmental toxicity
Saxagliptin has effects on fertility in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.
Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations (with dose-related increases in kidney weight and macroscopic kidney enlargement) were reported at all dose levels; pup exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.
Dapagliflozin dosed to maternal rats from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (at maternal and pup dapagliflozin exposures of 1 415 times and 137 times, respectively, the human values at the maximum recommended human dose [MRHD]). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day (pup exposures ≥ 29 times the human values at the MRHD). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The NOAEL for developmental toxicity is associated with a maternal systemic exposure 19 times the human values at the MRHD.
In studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternal nor developmental toxicities at any dose tested; the highest dose tested corresponded to a systemic exposure 1 191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1 441 times the human values at the MRHD.
6. |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Microcrystalline cellulose (E460i)
Croscarmellose sodium (E468)
Lactose
Magnesium stearate (E470b)
Dental type silica (E551)
Film-coating
Poly(vinyl alcohol) (E1203)
Macrogol (3350)
Titanium dioxide (E171)
Talc (E553b)
Iron oxide yellow (E172)
Iron oxide red (E172)
Printing ink
Shellac
Indigo carmine aluminium lake (E132)
6.2 |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
PA/Alu/PVC-Alu blister
Pack sizes of 14, 28, and 98 film-coated tablets in calendar blisters
Pack size of 30 film-coated tablets in blisters
Not all pack sizes may be marketed.
6.6 |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements.
7. |
Qtern 5 mg/10 mg film-coated tablets | Marketing authorisation holder | AstraZeneca UK Limited,
1 Francis Crick Avenue,
Cambridge,
CB2 0AA,
UK.
8. Marketing authorisation number(s)
PLGB 17901/0339
9. |
Qtern 5 mg/10 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 30 October 2021
10. |
Qtern 5 mg/10 mg film-coated tablets | Date of revision of the text | 24 November 2022 |
Haemaccel | Name of the medicinal product | Haemaccel
2. |
Haemaccel | Qualitative and quantitative composition | Haemaccel contains 35 g Polygeline as active ingredient in 1,000 ml.
Excipient(s) with known effect
Each 500ml vial contains 4.25g sodium chloride.
Each 500ml vial contains 0.20g potassium chloride.
For the full list of excipients, see section 6.1
3. |
Haemaccel | Pharmaceutical form | Solution for infusion
4. |
Haemaccel | Clinical particulars - Therapeutic indications | Therapeutic indications
1. As a plasma volume substitute in the initial treatment of hypovolaemic shock due to:
a) Haemorrhage (visible or concealed)
b) Burns, peritonitis, pancreatitis, crush injuries
2. Fluid replacement in plasma exchange
3. Extra-corporeal circulation
4. Isolated organ perfusion
5. As a carrier solution for insulin
4.2 |
Haemaccel | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Haemaccel should be administered intravenously in a volume approximately equal to the estimated blood loss.
See section 6.6. for Special precautions for disposal and other Handling.
Infusion rate:
The rate of infusion is determined by the condition of the patient. Normally, 500 ml will be infused in not less than 60 minutes but in emergencies Haemaccel can be rapidly infused. Losses of up to 25 % of the blood volume can be replaced by Haemaccel alone.
Hypovolaemic shock:
500 -1,000 ml Haemaccel should be infused intravenously initially.
Up to 1,500 ml blood loss can be replaced entirely by Haemaccel. For between 1,500 ml and 4,000 ml blood loss, fluid replacement should be with equal volumes of Haemaccel and blood given separately (see Pharmaceutical Precautions). For losses over 4,000 ml, the separate infusion should be in the ratio of two parts blood to one part Haemaccel. The Haematocrit should not be allowed to fall below 25 %.
Burns:
It is suggested that at least 1 ml Haemaccel be infused per kg of body weight. Multiplied by the % of body surface burned for each 24 hours for two days, e.g. if a 70 kg person has burns covering 10 % of body surface, then the dosage of Haemaccel should be at least 1 (ml) x 70 (kg) x 10 (%) = 700 ml/24 hours. Additional crystalloid solutions should be given to cover the normal fluid loss, i.e. about 2,000 ml per 24 hours. In severe burns additional protein and vitamin therapy may be required. The volume of colloid and crystalloid given should be varied according to the clinical response of the patient, the urine volume, its specific gravity and osmolality etc.
Plasma exchange:
Haemaccel should be given either alone or in combination with other replacement fluids in a volume adequate to replace the plasma removed.
Up to 2 litres have been given as sole replacement fluid.
Method of administration
Intravenous infusion.
4.3 |
Haemaccel | Clinical particulars - Contraindications | Contraindications
Haemaccel is contra-indicated in patients with a known hypersensitivity to constituents of the preparation and/or patients with existing anaphylactoid reactions.
4.4 |
Haemaccel | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
In the following cases, Haemaccel is indicated to a restricted extent only; if the physician considers the infusion necessary, it should be given taking special precautions.
All conditions in which an increase in intravascular volume and its consequences (e.g. increased stroke volume, elevated blood pressure), or an increase in interstitial fluid volume, or haemodilution could represent a special risk for the patient. Examples of such conditions are: congestive heart failure, hypertension, oesophageal varices, pulmonary oedema, haemorrhagic diathesis, renal and post-renal anuria.
In all patients at an increased risk of histamine release (e.g. allergic persons and patients with a history of histamine response; also patients who in the previous 7 days have received a drug which releases histamine). In the latter cases, Haemaccelmay be given only after taking appropriate prophylactic steps. Reactions caused by histamine release can be avoided by the prophylactic use of H1 and H2 receptor antagonists.
Inappropriate rapid administration of Haemaccel, especially to normovolaemic patients may cause the release of vasoactive substances. The exact mechanism of this histamine release has not been clearly defined.
Haemaccel contains sodium chloride and potassium chloride:
Haemaccel contains 4.25g sodium chloride & 0.20g potassium chloride per 500ml.
This medicinal product contains approximately 0.1847mmol sodium in each 500ml vial. This should be taken into consideration by patients on a controlled sodium diet.
This medicinal product contains approximately 0.005mmol potassium in each 500ml vial. This should be taken into consideration by patients on a controlled potassium diet.
4.5 |
Haemaccel | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Haemaccel contains calcium ions and caution should be observed in patients being treated with cardiac glycosides. Haemaccel may be mixed with other infusion solutions (e.g. saline, dextrose, Ringer's solution etc.) or with heparinised blood. Sterility must be maintained. Compatible water-soluble drugs may be infused in Haemaccel, e.g. insulin, streptokinase etc. Any additive should be injected into the bottle through a small hole located next to the pull-ring.
4.6 |
Haemaccel | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Haemorrhage around the time of childbirth or blood loss during other obstetric or gynaecological procedures may necessitate plasma volume replacement. Haemaccel has been used for many years for the initial treatment in such cases without apparent ill consequence.
If plasma volume replacement is needed during pregnancy, Haemaccel may be used if blood is not available.
4.7 |
Haemaccel | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Not applicable.
4.8 |
Haemaccel | Clinical particulars - Undesirable effects | Undesirable effects
During or after the infusion of volume-expanding solutions, transient urticarial skin reactions (wheals), hypotension, tachycardia, bradycardia, nausea/vomiting, dyspnoea, increases in temperature and/or shivering may occasionally occur.
Rare cases of severe hypersensitivity reactions including shock have been observed. Treatment will depend on the nature and severity of the reaction. Mild reactions: administer corticosteroids and antihistamines.
In the event of anaphylactic shock, the infusion should be discontinued and adrenalin (5-10 ml of 1:10,000 by slow i.v. injection or 0.5 -1.0 ml of 1:1,000 by i.m./s.c. injection) should immediately be given. Administration of adrenalin should be repeated every 15 minutes until improvement occurs. Circulatory collapse requires volume replacement, preferably monitored by a central venous pressure line. Large volumes of electrolyte solution may be necessary because, in severe anaphylactic shock, plasma loss may constitute up to 40 % of the plasma volume. A slow i.v. injection of an H1 antagonist such as 10 - 20 mg chlorpheniramine may be given.
Histamine release has been shown to be a cause of anaphylactic side-effects associated with infusions of Haemaccel.
These reactions may occur as a result of the cumulative effect of several histamine-releasing drugs (e.g. anaesthetics, muscle relaxants, analgesics, ganglia blockers and anticholinergic drugs).
Due to the calcium content of Haemaccel, the serum calcium concentrations may be found to be slightly elevated for a temporary period especially when large amounts of Haemaccel are administered by rapid infusion. So far, no reports have been received of cases involving clinical signs of hypercalcaemia resulting from an infusion of Haemaccel.
The infusion of Haemaccel may result in a temporary increase in the erythrocyte sedimentation rate.
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 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 |
Haemaccel | Clinical particulars - Overdose | Overdose
Not applicable.
5. Pharmacological properties
5.1 |
Haemaccel | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Haemaccel has a mean half-life of about 5 hours. About 74 % is excreted via the kidneys four days after administration.
It is metabolised into smaller peptides and amino acids by proteolytic enzymes.
5.3 |
Haemaccel | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
None.
6. |
Haemaccel | Pharmaceutical particulars - List of excipients | List of excipients
Sodium Chloride, Ph. Eur.
4.25 g;
Potassium Chloride, Ph. Eur.
0.20 g;
Calcium Chloride Ph. Eur.
0.466 g;
Water for Injections, Ph. Eur.
to 500 ml.
6.2 |
Haemaccel | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Citrated blood should NOT be mixed with Haemaccel since clotting of the blood may occur due to the presence of calcium ions in Haemaccel. However, citrated blood may be infused before or after Haemaccel provided that there is adequate flushing of the infusion set.
6.3 |
Haemaccel | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Haemaccel | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
None
6.5 |
Haemaccel | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
500 ml Polypropylene bottles.
Insocap (Polypropylene cap with elastomer liner)
6.6 |
Haemaccel | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
In common with all intravenous infusion, Haemaccel should, if possible, be warmed to body temperature before use.
However, in emergencies, it may be infused at ambient temperature. For technical reasons, there is a residual air volume in the container.
Thus, pressure infusions with the plastic infusion bottle must be carried out under controlled conditions only, as the risk of an air embolism cannot be excluded.
7. |
Haemaccel | Marketing authorisation holder | Piramal Critical Care Limited,
Suite 4, Ground Floor
Heathrow Boulevard - East Wing,
280 Bath Road, West Drayton, UB7 0DQ,
United Kingdom
8. Marketing authorisation number(s)
PL 37071/0022
9. |
Haemaccel | Date of first authorisation/renewal of the authorisation | 12th January 2005
10. |
Haemaccel | Date of revision of the text | 02/08/2019 |
Haemoctin | Name of the medicinal product | Haemoctin 250
Haemoctin 500
Haemoctin 1000
Powder and solvent for solution for injection
2. |
Haemoctin | Qualitative and quantitative composition | Human plasma derived coagulation factor VIII
One vial contains nominally 250, 500 or 1000 IU human plasma derived coagulation factor VIII.
Haemoctin 250 contains approximately 250 IU (50 IU/ml) human coagulation factor VIII after reconstitution.
Haemoctin 500 contains approximately 500 IU (100 IU/ml) human coagulation factor VIII after reconstitution.
Haemoctin 1000 contains approximately 1000 IU (200 IU/ml) human coagulation factor VIII after reconstitution.
The potency (IU) is determined using the European Pharmacopoeia chromogenic factor VIII coagulation assay. The specific activity of Haemoctin is approximately 100 IU/mg protein.
Produced from the plasma of human donors.
Excipient with known effect:
One vial contains up to 32.2 mg sodium (1.4 mmol).
For the full list of excipients, see section 6.1.
3. |
Haemoctin | Pharmaceutical form | Powder and solvent for solution for injection.
White powder and clear, colourless solvent for solution for injection.
4. |
Haemoctin | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).
This preparation does not contain von Willebrand factor in pharmacologically effective quantities and is therefore not indicated in von Willebrand´s disease.
4.2 |
Haemoctin | Clinical particulars - Posology and method of administration | Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Treatment monitoring
During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.
When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients' blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.
Posology
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient´s clinical condition.
The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO concentrate standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in International Units (relative to an International Standard for factor VIII in plasma).
One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma.
On demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1 % to 2 % of normal activity.
The required dose is determined using the following formula:
Required units = body weight (kg) x desired factor VIII rise (%) x 0.5
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
Degree of haemorrhage/ Type of surgical procedure
Factor VIII level required (%)
Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding
20 - 40
Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma
30 - 60
Repeat every 12 to 24 hours for 3 - 4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages
60 - 100
Repeat every 8 to 24 hours until threat is resolved.
Surgery
Minor surgery
including tooth extraction
30 - 60
Every 24 hours, at least 1 day, until healing is achieved.
Major surgery
80 - 100(pre- and post-operative)
Repeat every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30 - 60%.
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
Method of administration
Intravenous use. It is recommended not to administer more than 2-3 ml Haemoctin/min. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 |
Haemoctin | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 |
Haemoctin | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Traceability
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity
Allergic type hypersensitivity reactions are possible with Haemoctin. The product contains traces of human proteins other than factor VIII. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
Inhibitors
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon.
The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.
Cardiovascular events
In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase the cardiovascular risk.
Catheter-related complications
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV). The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived factor VIII products.
Paediatric population
The special warnings and precautions for use mentioned for the adults should also be considered for the paediatric population.
Sodium content
This medicinal product contains up to 32.2 mg sodium (1.4 mmol) per vial, equivalent to 1.61 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
4.5 |
Haemoctin | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
No interactions of human coagulation factor VIII products with other medicinal products have been reported.
4.6 |
Haemoctin | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.
4.7 |
Haemoctin | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Haemoctin has no or negligible influence on the ability to drive and use machines.
4.8 |
Haemoctin | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Haemoctin. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
For safety information with respect to transmissible agents, see section 4.4.
Tabulated list of adverse reactionsThe table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).
Frequencies have been evaluated according to the following convention: 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); very rare (<1/10,000), not known (cannot be estimated from the available data).
From clinical trials, non interventional studies, spontaneous reporting and regular literature screening the following adverse reactions were reported on Haemoctin:
MedDRA Standard System Organ Class
Adverse reactions
Frequency
Blood and lymphatic system disorders
Factor VIII inhibition
uncommon (PTPs)*
very common (PUPs)*
Immune system disorders
Anaphylactic shock, hypersensitivity
not known
Skin and subcutaneous tissue disorder
Erythema, pruritus, urticaria
not known
*Frequency is based on studies with all factor VIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients.
Paediatric population
With exception of factor VIII inhibition, adverse reactions in children are expected to be the same as in adults (see table above).
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 national reporting system: 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 |
Haemoctin | Clinical particulars - Overdose | Overdose
No case of overdose has been reported.
5. Pharmacological properties
5.1 |
Haemoctin | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Plasma factor VIII activity decreases by a two-phase exponential decay after intravenous use. In the initial phase, distribution between intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 1 to 8 hours. In the subsequent phase the half-life varies between 5 - 18 hours, with an average of about 12 hours. This appears to correspond to the true biological half-life.
The incremental recovery of Haemoctin is approximately 0.020 ± 0.003 IU/ml/IU/kg b.w. The level of factor VIII activity after intravenous use of 1 IU factor VIII per kg b.w. is about 2 %.
Other pharmacokinetic parameters of Haemoctin are:
• Area under the curve (AUC): about 17 IU x h / ml
• Mean residence time (MRT): about 15 h
• Clearance: about 155 ml/h.
5.3 |
Haemoctin | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Human plasma coagulation factor VIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous factor VIII. Single dose toxicity testing is of no relevance since higher doses result in overloading. Repeated dose toxicity testing in animals is impracticable due to the interference with developing antibodies to heterologous protein.
Even doses of several times the recommended human dose per kilogram body weight show no toxic effects on laboratory animals.
Since clinical experience provides no hint for tumorigenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered imperative.
6. |
Haemoctin | Pharmaceutical particulars - List of excipients | List of excipients
Powder: glycine, sodium chloride, sodium citrate, calcium chloride
Solvent: water for injections
6.2 |
Haemoctin | Pharmaceutical particulars - Incompatibilities | Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the provided infusion sets should be used because treatment failure can occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.
6.3 |
Haemoctin | Pharmaceutical particulars - Shelf life | Shelf life
2 years
After first opening, the product should be used immediately.
6.4 |
Haemoctin | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C. Do not freeze.
Keep the vials in the outer carton in order to protect from light.
6.5 |
Haemoctin | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
1 package Haemoctin contains:
1 vial (20 ml) with powder out of glass type I acc. to Ph. Eur.Freeze-drying stoppers out of halobutyl-caoutchouc, type I acc. to Ph. Eur.
1 vial with 5 ml solvent, glass type I acc. to Ph. Eur. Injection stoppers out of halobutyl-caoutchouc, type I acc. to Ph. Eur.
The pack also contains:
1 disposable syringe (5 ml), 1 transfer system with integral filter, 1 butterfly cannula
6.6 |
Haemoctin | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
Instructions for use and handling:
Absolute sterility is to be ensured in all steps of the procedure!
Dissolution of the concentrate:
• Bring the unopened vials of the solvent (water for injections) and product to room temperature. If a water bath is used for warming, it must be scrupulously ensured that the water does not come into contact with the caps or stoppers of the vials. Otherwise contamination of the medicine may occur.
• Very important for proper use of the transfer system: prior to opening, make sure that the white lower part of the transfer system sits directly on the ground of the blister (Fig. 1a: correct/ Fig. 1b: not correct). If not correct: push the transfer system down in the blister until the white lower part of the transfer system sits directly on the ground of the blister (Fig. 1c).
• Remove the caps from the solvent and the product vial in order to expose the central portions of the rubber stoppers (Fig. 2). Ensure that the rubber stoppers of the product and solvent vials are treated with a disinfectant.
• Remove the top of the transfer system packaging (Fig. 3).
• Place the solvent vial on even surface. Place the blue part of the transfer system within the blister straight onto the upright standing vial containing the solvent (Fig. 4). Do not twist the transfer system!
• Remove the remaining part of the blister from the transfer system. Do not squeeze the blister! Now the white part of the transfer system is visible (Fig. 5).
• Place the product vial on an even surface.
• Turn the combination of transfer system and solvent vial upside down. Push the spike of the white part of the adapter straight down through the product vial stopper (Fig. 6). The vacuum present in the product vial causes the solvent to flow into the product vial.
• Gently swirling the product vial helps in dissolving the powder. Do not shake vigorously, all foaming is to be avoided! The solution is clear or slightly opalescent.
• Afterwards unscrew the blue part of the transfer system together with the solvent vial counterclockwise (Fig. 7). Discard the solvent vial with the blue part of the transfer system attached. The Luer-Lock connector is now visible.
The solution ready for use should be used immediately after dissolving. Do not use solutions that are cloudy or contain visible particles.
Injection:
• Once you have dissolved the powder as described above, screw the enclosed syringe onto the Luer-Lock connector of the product vial with the white part of the transfer system (Fig. 8). This allows you to easily draw the dissolved drug into the syringe. A separate filter is not necessary because the transfer system has its own integral filter.
• Carefully disconnect the vial with the white part of the transfer system from the syringe. Use the enclosed butterfly needle and administer immediately by slow intravenous injection. The injection rate must not exceed 2-3 ml/minute.
• After the butterfly needle has been used, it can be made safe with the protective cap.
7. |
Haemoctin | Marketing authorisation holder | Biotest Pharma GmbH
Landsteinerstrasse 5
63303 Dreieich
Germany
Tel.: + 49 6103 801-0
Fax: + 49 6103 801-150
Email: [email protected]
8. Marketing authorisation number(s)
PL 04500/0009PL 04500/0010
9. |
Haemoctin | Date of first authorisation/renewal of the authorisation | 06/08/2008 and 04/09/2008 / 18/03/2013
10. |
Haemoctin | Date of revision of the text | 24/04/2023 |
Haemonine 500 / Haemonine 1000 | Name of the medicinal product | Haemonine® 500
Haemonine® 1000
Powder and solvent for solution for injection
2. |
Haemonine 500 / Haemonine 1000 | Qualitative and quantitative composition | Human plasma derived coagulation factor IX;
Haemonine® is presented as a powder and solvent for solution for injection containing either 500 or 1000 IU human coagulation factor IX per vial.
When reconstituted with either 5 ml or 10 ml water for injections, Haemonine® contains approximately 100 IU/ml human coagulation factor IX.
The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. The specific activity of Haemonine® is ≥ 70 IU/mg protein.
Excipients with known effect: The reconstituted product contains 0.19 mmol – 0,245 mmol (4.37 mg – 5,63 mg) sodium per ml. For the full list of excipients, see section 6.1.
3. |
Haemonine 500 / Haemonine 1000 | Pharmaceutical form | Powder and solvent for solution for injection.
White powder and clear, colourless solvent for solution for injection.
After dissolving the powder in the provided water for injections, the Haemonine solution is clear or slightly opalescent without any visible particles (see section 6.6).
4. |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
Haemonine is indicated in adults, adolescents and children aged 6 years and older.
4.2 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Posology and method of administration | Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Treatment monitoring
During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.
Posology
Dose and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient´s clinical condition.
The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.
On demand treatment
The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1-2 % of normal activity. The required dose is determined using the following formula:
Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x 0.8
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
Degree of haemorrhage/ Type of surgical procedure
Factor IX level required (%) (IU/dl)
Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding
20 - 40
Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma
30 - 60
Repeat infusion every 24 hours for 3 - 4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages
60 - 100
Repeat infusion every 8 to 24 hours until threat is resolved.
Surgery
Minor surgery
including tooth extraction
30 - 60
Every 24 hours, at least 1 day, until healing is achieved.
Major surgery
80 - 100(pre- and post-operative)
Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30 to 60% (IU/dl).
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kilogram of body weight at intervals of 3 to 4 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
Paediatric population
There are insufficient data to recommend the use of Haemonine® in children less then 6 years of age.
Method of administration
Intravenous use.
For instructions on dilution of the medicinal product before administration, see section 6.6. It is recommended to not exceed a maximal infusion rate of 5 ml/min.
4.3 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to heparin.
4.4 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Hypersensitivity
Allergic type hypersensitivity reactions are possible with Haemonine. The product contains traces of human proteins other than factor IX. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria tightness of chest, wheezing, hypotension, and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
Inhibitors
After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
Thromboembolism
Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Haemonine should be weighed against the risk of these complications.
Due to potential additive or synergistic pharmacodynamic effects, coadministration of antifibrinolytic agents with anti-inhibitor coagulant complex or factor IX complex could increase the risk of thrombosis.
Cardiovascular events
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
Catheter-related complications
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV).
The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived factor IX products.
It is strongly recommended that every time that Haemonine® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
Paediatric population
The listed warnings and precautions apply both to adults and children aged 6 years and older (see also section 4.2).
This medicinal product contains a maximum of 4.9 mmol (113 mg) sodium per standard dose of 2000 IU. To be taken into consideration by patients on a controlled sodium diet.
4.5 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. No interactions of human coagulation factor IX products with other medicinal products have been reported.
Paediatric population
The listed interactions apply both to adults and children aged 6 years and older (see also section 4.2).
4.6 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Fertility data are not available.
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available. Therefore, factor IX should be used during pregnancy and lactation only if clearly indicated.
4.7 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Haemonine has no or negligible influence on the ability to drive and use machines.
4.8 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, , generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also section 4.4).
Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Haemonine may contain traces of heparin below the limit of quantitation (0.1 IU/ml) which may cause hypersensitivity reactions and reduced blood cell counts which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such side effects.
For safety information with respect to transmissible agents, see section 4.4.
Tabulated list of adverse reactions
Frequencies have been evaluated according to the following convention:
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
Very rare:
<1/10,000
not known
cannot be estimated from the available data
Frequency of Adverse Drug Reactions (ADRs) in clinical studies with Haemonine (Frequencies are calculated per patients treated (n=36)):
MedDRA Standard System Organ Class
Frequency
Adverse reactions
Immune system disorders
very common*
Hypersensitivity
Psychiatric disorders
common
Anxiety
Nervous system disorders
common
Hyperaesthesia
Gastrointestinal disorders
common
Nausea
Skin and subcutaneous tissue disorders
common
Dermatitis allergic, Urticaria
Musculoskeletal and connective tissue disorders
common
Back pain
Vascular disorders
common
Hot flush
Respiratory, thoracic and mediastinal disorders
common
Dyspnoea
General disorders and administration site conditions
common
Feeling cold, Injection site reaction (including e.g. pain and rash)
Investigations
not known**
factor IX inhibition
* Hypersensitivity can be allergic or non-allergic reactions. True allergic reactions are rare.
** Reported from post-marketing sources.
Description of selected adverse reactions
Factor IX inhibition
The development of inhibitory antibodies is a known complication in the management of individuals with haemophilia B. There is no experience with previously untreated patients (PUPs) so far.
During clinical development no factor IX inhibitor induction was observed in previously treated patients (PTPs, n=36) during 1,493 exposure days.
Paediatric population
Frequency, type and severity of adverse reactions in children aged 6 years and older are expected to be the same as in adults (see also section 4.2).
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 national reporting system listed in Appendix V*.
4.9 |
Haemonine 500 / Haemonine 1000 | Clinical particulars - Overdose | Overdose
No case of overdose has been reported.
5. Pharmacological properties
5.1 |
Haemonine 500 / Haemonine 1000 | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
A pharmacokinetic study with 13 patients yielded the following results:
Using a biphasic model the mean initial half-life was 2.2 ± 1.9 h at initial visit and 3.1 ± 2.9 h at month 3, respectively. The mean terminal half-life was calculated as 28.5 ± 12.1 h at initial visit and 30.1 ± 14.7 h at month 3. The incremental recovery of Haemonine® was 69.8 ± 21.6 % and 72.2 ± 22.2 % at initial visit and at month 3, respectively. This corresponded to an incremental recovery of 0.015 ± 0.005 IU/ml/IU/kg body weight at initial visit and of 0.016 ± 0.005 IU/ml/IU/kg body weight at month 3. Other pharmacokinetic parameters of Haemonine® are: Area under the curve (AUC): about 25 IU · h/ml; Mean residence time (MRT): about 33 h; Clearance: about 200 ml/h.
5.3 |
Haemonine 500 / Haemonine 1000 | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
The preparation contains exclusively human plasma derived proteins, namely high purity coagulation factor IX, which is identical with the endogenous factor IX.
Preclinical studies in an Ames test showed no mutagenic potential of the preparation.
Haemonine® was tested for abnormal toxicity and thrombogenic potential in different rabbit models. The results revealed no signs for toxicological or thrombogenic potential.
6. |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - List of excipients | List of excipients
Powder:
arginine
lysine
sodium chloride
sodium citrate
Solvent:
water for injections.
6.2 |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - Incompatibilities | Incompatibilities
This medicinal product must not be mixed with other medicinal products.
Use only the provided injection sets because treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some injection equipment.
6.3 |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - Shelf life | Shelf life
2 years
Use immediately after reconstitution.
6.4 |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25°C.
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
6.5 |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
1 package Haemonine® 500 contains:1 vial with powder, glass type I (Ph.Eur.), closed with chlorobutyl rubber stopper, type I (Ph.Eur.)
1 vial with solvent (5 ml), glass type I (Ph.Eur.), closed with bromobutyl rubber stopper, type I (Ph.Eur.)
The pack also contains: 1 disposable syringe (5 ml), 1 double-filter transfer system, 1 butterfly cannula.
1 package Haemonine® 1000 contains:1 vial with powder, glass type I (Ph.Eur.), closed with chlorobutyl rubber stopper, type I (Ph.Eur.)
1 vial with solvent (10 ml), glass type I (Ph.Eur.), closed with bromobutyl rubber stopper, type I (Ph.Eur.)
The pack also contains: 1 disposable syringe (10 ml), 1 double-filter transfer system, 1 butterfly cannula.
6.6 |
Haemonine 500 / Haemonine 1000 | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Absolute sterility is to be ensured in all steps of the procedure !
Dissolution of the concentrate:
• Bring the unopened vials of the solvent (water for injections) and product to room temperature. If a water bath is used for warming, it must be scrupulously ensured that the water does not come into contact with the caps or stoppers of the vials. Otherwise contamination of the medicine may occur.
• Very important for proper use of the transfer system: prior to opening, make sure that the white lower part of the transfer system sits directly on the ground of the blister (Fig. 1a: correct/ Fig. 1b: not correct). If not correct: push the transfer system down in the blister until the white lower part of the transfer system sits directly on the ground of the blister (Fig. 1c).
• Remove the caps from the solvent and the product vial in order to expose the central portions of the rubber stoppers (Fig. 2). Ensure that the rubber stoppers of the product and solvent vials are treated with a disinfectant.
• Remove the top of the transfer system packaging (Fig. 3).
• Place the solvent vial on even surface. Place the blue part of the transfer system within the blister straight onto the upright standing vial containing the solvent (Fig. 4). Do not twist the transfer system!
• Remove the remaining part of the blister from the transfer system. Do not squeeze the blister! Now the white part of the transfer system is visible (Fig. 5).
• Place the product vial on an even surface.
• Turn the combination of transfer system and solvent vial upside down. Push the spike of the white part of the adapter straight down through the product vial stopper (Fig. 6). The vacuum present in the product vial causes the solvent to flow into the product vial.
• Gently swirling the product vial helps in dissolving the powder. Do not shake vigorously, all foaming is to be avoided! The solution is clear or slightly opalescent.
• Afterwards unscrew the blue part of the transfer system together with the solvent vial counterclockwise (Fig. 7). Discard the solvent vial with the blue part of the transfer system attached. The Luer-Lock connector is now visible.
The solution ready for use should be used immediately after dissolving. Do not use solutions that are cloudy or contain visible particles.
Injection:
• Once you have dissolved the powder as described above, screw the enclosed syringe onto the Luer-Lock connector of the product vial with the white part of the transfer system (Fig. 8). This allows you to easily draw the dissolved drug into the syringe. A separate filter is not necessary because the transfer system has its own integral filter.
• Carefully disconnect the vial with the white part of the transfer system from the syringe. Use the enclosed butterfly needle and administer immediately by slow intravenous injection. The injection rate must not exceed 2-3 ml/minute.
• After the butterfly needle has been used, it can be made safe with the protective cap.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. |
Haemonine 500 / Haemonine 1000 | Marketing authorisation holder | Biotest Pharma GmbH
Landsteinerstrasse 5
63303 Dreieich
Germany
Phone: +49 6103 801-0
Fax: +49 6103 801-150
Email: [email protected]
8. Marketing authorisation number(s)
PL 04500/0008
9. |
Haemonine 500 / Haemonine 1000 | Date of first authorisation/renewal of the authorisation | 19/12/2008
10. |
Haemonine 500 / Haemonine 1000 | Date of revision of the text | 11/05/2023 |
Halaven 0.44 mg/ml solution for injection | Name of the medicinal product | HALAVEN 0.44 mg/ml solution for injection
2. |
Halaven 0.44 mg/ml solution for injection | Qualitative and quantitative composition | One ml contains eribulin mesilate equivalent to 0.44 mg eribulin.
Each 2 ml vial contains eribulin mesilate equivalent to 0.88 mg eribulin.
For the full list of excipients, see section 6.1.
3. |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical form | Solution for injection (injection).
Clear, colourless aqueous solution.
4. |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Therapeutic indications | Therapeutic indications
HALAVEN is indicated for the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease (see section 5.1). Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments.
HALAVEN is indicated for the treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease (see section 5.1).
4.2 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Posology and method of administration | Posology and method of administration
HALAVEN should only be prescribed by a qualified physician experienced in the appropriate use of anti-cancer therapy. It should be administered by an appropriately qualified healthcare professional only.
Posology
The recommended dose of eribulin as the ready to use solution is 1.23 mg/m2 which should be administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle.
Please note:
In the EU the recommended dose refers to the base of the active substance (eribulin). Calculation of the individual dose to be administered to a patient must be based on the strength of the ready to use solution that contains 0.44 mg/ml eribulin and the dose recommendation of 1.23 mg/m2. The dose reduction recommendations shown below are also shown as the dose of eribulin to be administered based on the strength of the ready to use solution.
In the pivotal trials, the corresponding publications and in some other regions e.g. the United States and Switzerland, the recommended dose is based on the salt form (eribulin mesilate).
Patients may experience nausea or vomiting. Antiemetic prophylaxis including corticosteroids should be considered.
Dose delays during therapy
The administration of HALAVEN should be delayed on Day 1 or Day 8 for any of the following:
- Absolute neutrophil count (ANC) < 1 x 109/l
- Platelets < 75 x 109/l
- Grade 3 or 4 non-hematological toxicities.
Dose reduction during therapy
Dose reduction recommendations for retreatment are shown in the following table.
Dose reduction recommendations
Adverse reaction after previous HALAVEN administration
Recommended dose of eribulin
Haematological:
ANC < 0.5 x 109/l lasting more than 7 days
0.97 mg/m2
ANC < 1 x 109/l neutropenia complicated by fever or infection
Platelets < 25 x 109/l thrombocytopenia
Platelets < 50 x 109/l thrombocytopenia complicated by haemorrhage or requiring blood or platelet transfusion
Non-haematological:
Any Grade 3 or 4 in the previous cycle
Reoccurrence of any haematological or non-haematological adverse reactions as specified above
Despite reduction to 0.97 mg/m2
0.62 mg/m2
Despite reduction to 0.62 mg/m2
Consider discontinuation
The dose of eribulin should not be re-escalated after it has been reduced.
Patients with hepatic impairment
Impaired liver function due to metastases
The recommended dose of eribulin in patients with mild hepatic impairment (Child-Pugh A) is 0.97 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of eribulin in patients with moderate hepatic impairment (Child-Pugh B) is 0.62 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
Severe hepatic impairment (Child-Pugh C) has not been studied but it is expected that a more marked dose reduction is needed if eribulin is used in these patients.
Impaired liver function due to cirrhosis
This patient group has not been studied. The doses above may be used in mild and moderate impairment but close monitoring is advised as the doses may need readjustment.
Patients with renal impairment
Some patients with moderately or severely impaired renal function (creatinine clearance <50 ml/min) may have increased eribulin exposure and may need a reduction of the dose. For all patients with renal impairment, caution and close safety monitoring is advised. (See section 5.2)
Elderly patients
No specific dose adjustments are recommended based on the age of the patient (see section 4.8).
Paediatric population
There is no relevant use of HALAVEN in children and adolescents for the indication of breast cancer.
There is no relevant use of HALAVEN in the paediatric population for the indication of soft tissue sarcoma (see section 5.1).
Method of administration
HALAVEN is for intravenous use. The dose may be diluted in up to 100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. It should not be diluted in glucose 5% infusion solution. For instructions on the dilution of the medicinal product before administration, see section 6.6. Good peripheral venous access, or a patent central line, should be ensured prior to administration. There is no evidence that eribulin mesilate is a vesicant or an irritant. In the event of extravasation, treatment should be symptomatic. For information relevant to the handling of cytotoxic medicinal products see section 6.6.
4.3 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Contraindications | Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Breast-feeding
4.4 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Haematology
Myelosuppression is dose dependent and primarily manifested as neutropenia (section 4.8). Monitoring of complete blood counts should be performed on all patients prior to each dose of eribulin. Treatment with eribulin should only be initiated in patients with ANC values ≥ 1.5 x 109/l and platelets > 100 x 109/l.
Febrile neutropenia occurred in < 5% of patients treated with eribulin. Patients experiencing febrile neutropenia, severe neutropenia or thrombocytopenia, should be treated according to the recommendations in section 4.2.
Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Although data are limited, patients with bilirubin >1.5 x ULN also have a higher incidence of Grade 4 neutropenia and febrile neutropenia.
Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported.
Severe neutropenia may be managed by the use of granulocyte colony-stimulating factor (G-CSF) or equivalent at the physician's discretion in accordance with relevant guidelines (see section 5.1).
Peripheral neuropathy
Patients should be closely monitored for signs of peripheral motor and sensory neuropathy. The development of severe peripheral neurotoxicity requires a delay or reduction of dose (see section 4.2)
In clinical trials, patients with pre-existing neuropathy greater than Grade 2 were excluded. However, patients with pre-existing neuropathy Grade 1 or 2 were no more likely to develop new or worsening symptoms than those who entered the study without the condition.
QT prolongation
In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias or concomittant treatment with medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to initiating HALAVEN and these electrolytes should be monitored periodically during therapy. Eribulin should be avoided in patients with congenital long QT syndrome.
Excipients
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
4.5 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved in this process is unknown. Eribulin is not a substrate of breast cancer resistance protein (BCRP), organic anion (OAT1, OAT3, OATP1B1, OATP1B3), multi-drug resistance-associated protein (MRP2, MRP4) and bile salt export pump (BSEP) transporters.
No drug-drug interactions are expected with CYP3A4 inhibitors and inducers. Eribulin exposure (AUC and Cmax) was unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and rifampicin, a CYP3A4 inducer.
Effects of eribulin on the pharmacokinetics of other medicines
In vitro data indicate that eribulin is a mild inhibitor of the important drug metabolising enzyme CYP3A4. No in vivo data are available. Caution and monitoring for adverse events is recommended with concomitant use of substances that have a narrow therapeutic window and that are eliminated mainly via CYP3A4-mediated metabolism (eg alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).
Eribulin does not inhibit the CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 at relevant clinical concentrations.
At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 transporter-mediated activity.
4.6 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, and teratogenic in rats. HALAVEN should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus.
Women of childbearing potential must be advised to avoid becoming pregnant whilst they or their male partner are receiving HALAVEN and have to use effective contraception during and up to 3 months after treatment.
Breast-feeding
It is unknown whether eribulin/metabolites are excreted in human or animal breast milk. A risk to newborns/infants cannot be excluded and therefore HALAVEN must not be used during breast-feeding (see section 4.3).
Fertility
Testicular toxicity has been observed in rats and dogs (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with HALAVEN.
4.7 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
HALAVEN may cause adverse reactions such as tiredness and dizziness which may lead to minor or moderate influence on the ability to drive or use machines. Patients should be advised not to drive or use machines if they feel tired or dizzy.
4.8 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Undesirable effects | Undesirable effects
Summary of safety profile
The most commonly reported adverse reactions related to HALAVEN, are bone marrow suppression manifested as neutropenia, leucopenia, anaemia, thrombocytopenia with associated infections. New onset or worsening of pre-existing peripheral neuropathy has also been reported. Gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, and stomatitis are among reported undesirable effects. Other undesirable effects include fatigue, alopecia, increased liver enzymes, sepsis and musculoskeletal pain syndrome.
Tabulated list of adverse reactions
Unless otherwise noted, the table shows the incidence rates of adverse reactions observed in breast cancer and soft tissue sarcoma patients who received the recommended dose in Phase 2 and Phase 3 studies.
Frequency categories are defined as: 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 very rare (< 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Where Grade 3 or 4 reactions occurred, the actual total frequency and the frequency of Grade 3 or 4 reactions are given.
System Organ Class
Adverse Reactions – all Grades
Very Common
(Frequency %)
Common
(Frequency %)
Uncommon
(Frequency %)
Rare or not known
Infections and infestations
Urinary tract infection (8.5%) (G3/4: 0.7%)
Pneumonia (1.6%) (G3/4: 1.0%)
Oral candidiasis
Oral herpes
Upper respiratory tract infection
Nasopharyngitis
Rhinitis
Herpes zoster
Sepsis (0.5%) (G3/4: 0.5%)a
Neutropenic sepsis (0.2%) (G3/4: 0.2%)a
Septic Shock (0.2%) (G3/4:0.2%)a
Blood and lymphatic system disorders
Neutropenia (53.6%) (G3/4: 46.0%)
Leukopenia (27.9%) (G3/4: 17.0%)
Anaemia (21.8%) (G3/4: 3.0%)
Lymphopenia (5.7%) (G3/4: 2.1%)
Febrile neutropenia (4.5%) (G3/4: 4.4%)a
Thrombocytopenia (4.2%) (G3/4: 0.7%)
*Disseminated intravascular coagulationb
Metabolism and nutrition disorders
Decreased appetite (22.5%) (G3/4: 0.7%)d
Hypokalaemia (6.8%) (G3/4: 2.0%) Hypomagnesaemia (2.8%) (G3/4: 0.3%)Dehydration (2.8 %) (G3/4: 0.5%)d
Hyperglycaemia
Hypophosphataemia
Hypocalcaemia
Psychiatric disorders
Insomnia
Depression
Nervous system disorders
Peripheral neuropathyc (35.9%) (G3/4: 7.3%)Headache (17.5%) (G3/4: 0.7%)
Dysgeusia
Dizziness (9.0%) (G3/4: 0.4%)d
Hypoaesthesia
Lethargy
Neurotoxicity
Eye disorders
Lacrimation increased (5.8%) (G3/4: 0.1%)d
Conjunctivitis
Ear and labyrinth disorders
Vertigo
Tinnitus
Cardiac disorders
Tachycardia
Vascular disorders
Hot flush
Pulmonary embolism (1.3%) (G3/4: 1.1%)a
Deep vein thrombosis
Respiratory, thoracic and mediastinal disorders
Dyspnoea (15.2%)a (G3/4: 3.5%)a
Cough (15.0%) (G3/4: 0.5%)d
Oropharyngeal pain
Epistaxis
Rhinorrhoea
Interstitial lung disease (0.2%) (G3/4: 0.1%)
Gastrointestinal disorders
Nausea (35.7%) (G3/4: 1.1%)d
Constipation (22.3%) (G3/4: 0.7%)dDiarrhoea (18.7%) (G3/4: 0.8%)
Vomiting (18.1%) (G3/4: 1.0%)
Abdominal pain Stomatitis (11.1%) (G3/4: 1.0%)d
Dry mouth Dyspepsia (6.5%) (G3/4: 0.3%)d
Gastrooesophageal reflux disease
Abdominal distension
Mouth ulceration
Pancreatitis
Hepatobiliary disorders
Aspartate aminotransferase increased (7.7%) (G3/4: 1.4%)d
Alanine aminotransferase increased (7.6%) (G3/4: 1.9%)d
Gamma glutamyl transferase increased (1.7%) (G3/4: 0.9%)d
Hyperbilirubinaemia (1.4%) (G3/4: 0.4%)
Hepatotoxicity (0.8%) (G3/4: 0.6%)
Skin and subcutaneous tissue disorders
Alopecia
Rash (4.9%) (G3/4: 0.1%)
Pruritus (3.9%) (G3/4: 0.1%)d
Nail disorder
Night sweats
Dry skin
Erythema
Hyperhidrosis
Palmar plantar erythrodysaesthesia (1.0%) (G3/4: 0.1%)d
Angioedema
**Stevens-Johnson syndrome/ Toxic epidermal necrolysisb
Musculoskeletal and connective tissue disorders
Arthralgia and myalgia (20.4%) (G3/4: 1.0%)
Back pain (12.8%) (G3/4: 1.5%)
Pain in extremity (10.0%) (G3/4: 0.7%)d
Bone pain (6.7%) (G3/4: 1.2%)
Muscle spasms (5.3%) (G3/4: 0.1%)d
Musculoskeletal pain
Musculoskeletal chest pain
Muscular weakness
Renal and urinary disorders
Dysuria
Haematuria
Proteinuria
Renal failure
General disorders and administration site conditions
Fatigue/Asthenia (53.2%) (G3/4 : 7.7%)Pyrexia (21.8%) (G3/4: 0.7%)
Mucosal Inflammation (6.4%) (G3/4: 0.9%)d
Peripheral oedema
Pain
Chills
Chest pain
Influenza like illness
Investigations
Weight decreased (11.4%) (G3/4: 0.4%)d
a Includes Grade 5 events.
b From spontaneous reporting
c Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating polyneuropathy
d No Grade 4 events
* Rare
** Frequency not known
Overall, the safety profiles in the breast cancer and soft tissue sarcoma patient populations were similar.
Description of selected adverse reactions
Neutropenia
The neutropenia observed was reversible and not cumulative; the mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (< 0.5 x 109/l) was 8 days.
Neutrophil counts of < 0.5 x 109/l that lasted for more than 7 days occurred in 13% of breast cancer patients treated with eribulin in the EMBRACE study.
Neutropenia was reported as a Treatment Emergent Adverse Event (TEAE) in 151/404 (37.4% for all grades) in the sarcoma population, compared with 902/1559 (57.9% for all grades) in the breast cancer population. The combined grouped TEAE and neutrophil laboratory abnormality frequencies were 307/404 (76.0%) and 1314/1559 (84.3%), respectively. The median duration of treatment was 12.0 weeks for sarcoma patients and 15.9 weeks for breast cancer patients.
Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported. Out of 1963 breast cancer and soft tissue sarcoma patients who received eribulin at the recommended dose in clinical trials there was one fatal event each of neutropenic sepsis (0.1%) and febrile neutropenia (0.1%). In addition there were 3 fatal events of sepsis (0.2%) and one of septic shock (0.1%).
Severe neutropenia may be managed by the use of G-CSF or equivalent at the physician's discretion in accordance with relevant guidelines. 18% and 13% of eribulin treated patients received G-CSF in the two phase 3 breast cancer studies (Studies 305 and 301, respectively). In the phase 3 sarcoma study (Study 309), 26% of the eribulin treated patients received G-CSF.
Neutropenia resulted in discontinuation in < 1% of patients receiving eribulin.
Disseminated intravascular coagulation
Cases of disseminated intravascular coagulation have been reported, typically in association with neutropenia and/or sepsis.
Peripheral neuropathy
In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with eribulin was peripheral neuropathy (3.4%). The median time to Grade 2 peripheral neuropathy was 12.6 weeks (post 4 cycles). Out of the 404 sarcoma patients, 2 patients discontinued treatment with eribulin due to peripheral neuropathy. The median time to Grade 2 peripheral neuropathy was 18.4 weeks.
Development of Grade 3 or 4 peripheral neuropathy occurred in 7.4% of breast cancer patients and 3.5% of sarcoma patients. In clinical trials, patients with pre-existing neuropathy were as likely to develop new or worsening symptoms as those who entered the study without the condition.
In breast cancer patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent Grade 3 peripheral neuropathy was 14%.
Hepatotoxicity
In some patients with normal/abnormal liver enzymes prior treatment with eribulin, increased levels of liver enzymes have been reported with initiation of eribulin treatment. Such elevations appeared to have occurred early with eribulin treatment in cycle 1 – 2 for the majority of these patients and whilst thought likely to be a phenomenon of adaptation to eribulin treatment by the liver and not a sign of significant liver toxicity in most patients, hepatotoxicity has also been reported.
Special populations
Elderly population
Of the 1559 breast cancer patients treated with the recommended dose of eribulin, 283 patients (18.2%) were ≥ 65 years of age. In the 404 sarcoma patient population, 90 patients (22.3%) treated with eribulin were ≥ 65 years of age. The safety profile of eribulin in elderly patients (≥ 65 years of age) was similar to that of patients <65 years of age except for asthenia/fatigue which showed an increasing trend with age. No dose adjustments are recommended for the elderly population.
Patients with hepatic impairment
Patients with ALT or AST > 3 x ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Although data are limited, patients with bilirubin > 1.5 x ULN also have a higher incidence of Grade 4 neutropenia and febrile neutropenia (see also sections 4.2 and 5.2).
Paediatric population
Three open-label studies, Studies 113, 213 and 223, were conducted in paediatric patients with refractory or recurrent solid tumours and lymphomas, but excluding central nervous system (CNS) tumours (see section 5.1).
The safety of eribulin monotherapy was evaluated in 43 paediatric patients who received up to 1.58 mg/m2 on Days 1 and 8 of a 21-day cycle (Studies 113 and 223). The safety of eribulin in combination with irinotecan was also evaluated in 40 paediatric patients who received eribulin 1.23 mg/m2 on Days 1 and 8 and irinotecan 20 or 40 mg/m2 on Days 1 to 5 of a 21-day cycle, or 100 or 125 mg/m2 on Days 1 and 8 of a 21-day cycle (Study 213).
In Study 113 (Phase 1), the most frequently reported adverse drug reactions were white blood cell count decreased, lymphocyte count decreased, anaemia and neutrophil count decreased.
In Study 213 (Phase 1/2), the most frequently reported adverse drug reactions were neutropenia (Phase 1) and diarrhoea and neutrophil count decreased (Phase 2).
In Study 223 (Phase 2), the most frequently reported adverse drug reactions were neutrophil count decreased, anaemia, and white blood cell count decreased.
The safety profile of eribulin as monotherapy or in combination with irinotecan hydrochloride in this paediatric population was consistent with the known safety profile of either study drug in the adult population.
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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Halaven 0.44 mg/ml solution for injection | Clinical particulars - Overdose | Overdose
In one case of overdose the patient inadvertently received 7.6 mg of eribulin (approximately 4 times the planned dose) and subsequently developed a hypersensitivity reaction (Grade 3) on Day 3 and neutropenia (Grade 3) on Day 7. Both adverse reactions resolved with supportive care.
There is no known antidote for eribulin overdose. In the event of an overdose, the patient should be closely monitored. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.
5. Pharmacological properties
5.1 |
Halaven 0.44 mg/ml solution for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Distribution
The pharmacokinetics of eribulin are characterized by a rapid distribution phase followed by a prolonged elimination phase, with a mean terminal half-life of approximately 40 h. It has a large volume of distribution (range of means 43 to 114 l/m2).
Eribulin is weakly bound to plasma proteins. The plasma protein binding of eribulin (100-1000 ng/ml) ranged from 49% to 65% in human plasma.
Biotransformation
Unchanged eribulin was the major circulating species in plasma following administration of 14C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.
Elimination
Eribulin has a low clearance (range of means 1.16 to 2.42 l/h/m2). No significant accumulation of eribulin is observed on weekly administration. The pharmacokinetic properties are not dose or time dependent in the range of eribulin doses of 0.22 to 3.53 mg/m2.
Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical in vitro studies indicate that eribulin is transported by Pgp. However it has been shown that at clinically relevant concentrations eribulin is not a Pgp inhibitor in vitro. Additionally, in vivo, concomitant administration of ketoconazole, a Pgp inhibitor, has no effect on eribulin exposure (AUC and Cmax). In vitro studies have also indicated that eribulin is not a substrate for OCT1.
After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in faeces and 9% in urine indicating that renal clearance is not a significant route of eribulin elimination.
Unchanged eribulin represented most of the total radioactivity in faeces and urine.
Hepatic impairment
A study evaluated the pharmacokinetics of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 0.97 mg/m2 to patients with mild hepatic impairment and 0.62 mg/m2 to patients with moderate hepatic impairment resulted in a somewhat higher exposure than after a dose of 1.23 mg/m2 to patients with normal hepatic function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). There is no study in patients with hepatic impairment due to cirrhosis. See section 4.2 for dosage recommendation.
Renal impairment
Increased eribulin exposure was seen in some patients with moderately or severely impaired renal function, with high between-subject variability. The pharmacokinetics of eribulin were evaluated in a Phase 1 study in patients with normal renal function (Creatinine clearance: ≥ 80 ml/min; n=6), moderate (30-50 ml/min; n=7) or severe (15-<30 ml/min; n=6) renal impairment. Creatinine clearance was estimated with the Cockcroft-Gault formula. A 1.5-fold (90% CI: 0.9-2.5) higher dose-normalised AUC(0-inf) was observed in patients with moderate and severe renal impairment. See section 4.2 for treatment recommendations.
Paediatric population
Eribulin plasma concentrations were collected from 83 paediatric patients (age range: 2 to 17 years), with refractory/relapsed and recurrent solid tumours and lymphomas, who received eribulin in Studies 113, 213 and 223. Eribulin PK in paediatric patients was comparable to adult patients with STS and patients with other types of tumour. Eribulin exposure in paediatric patients was similar to exposure in adult patients. Concomitant irinotecan did not have an effect on eribulin PK in paediatric patients with refractory/relapsed and recurrent solid tumours.
5.3 |
Halaven 0.44 mg/ml solution for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Eribulin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Eribulin was positive in the mouse lymphoma mutagenesis assay and was clastogenic in the in vivo rat micronucleus assay.
No carcinogenicity studies have been conducted with eribulin.
A fertility study was not conducted with eribulin, but based on non-clinical findings in repeated-dose studies where testicular toxicity was observed in both rats (hypocellularity of seminiferous epithelium with hypospermia/aspermia) and dogs, male fertility may be compromised by treatment with eribulin. An embryofoetal development study in rat confirmed the developmental toxicity and teratogenic potential of eribulin. Pregnant rats were treated with eribulin mesilate equivalent to 0.009, 0.027, 0.088 and 0.133 mg/kg eribulin at gestation days 8, 10 and 12. Dose related increased number of resorptions and decreased foetal weight were observed at doses ≥ 0.088 mg/kg and increased incidence of malformations (absence of lower jaw, tongue, stomach and spleen) was recorded at 0.133 mg/kg.
6. |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - List of excipients | List of excipients
Ethanol anhydrous
Water for injections
Hydrochloric acid (for pH-adjustment)
Sodium hydroxide (for pH-adjustment)
6.2 |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - Shelf life | Shelf life
Unopened vials
5 years.
In-use shelf life
From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Chemical and physical in-use stability of HALAVEN as an undiluted solution in a syringe has been demonstrated for up to 4 hours at 15-25°C and ambient lighting or up to 24 hours at 2°C - 8°C.
Chemical and physical in-use stability of HALAVEN as a diluted solution (0.018 mg/mL to 0.18 mg/mL eribulin in sodium chloride 9 mg/mL (0.9%) has been demonstrated for up to 72 hours at 2°C - 8°C.
6.4 |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening or dilution of the medicinal product, see section 6.3.
6.5 |
Halaven 0.44 mg/ml solution for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
5 ml type I glass vial, with teflon-coated, butyl rubber stopper and flip-off aluminium over seal, containing 2 ml of solution.
The pack sizes are cartons of 1 or 6 vials.
Not all pack sizes may be marketed.
6.6 |
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