Takhzyro

Lanadelumab.

One unit (pre-filled syringe) contains 300 mg of lanadelumab* in 2 mL solution.
*Lanadelumab is produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
The solution has a pH of approximately 6.0 and an osmolality of approximately 300 mOsm/kg.
Excipients/Inactive Ingredients: Disodium phosphate dihydrate, Citric acid monohydrate, Histidine, Sodium chloride, Polysorbate 80, Water for injections.

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema. ATC code: B06AC05.
Pharmacology: Pharmacodynamics: Mechanism of action: Lanadelumab is a fully human, monoclonal antibody (IgG1/ κ-light chain). Lanadelumab inhibits active plasma kallikrein proteolytic activity. Increased plasma kallikrein activity leads to angioedema attacks in patients with HAE through the proteolysis of high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin.
Lanadelumab provides sustained control of plasma kallikrein activity and thereby limits bradykinin generation in patients with HAE.
Pharmacodynamic effects: Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after SC administration of TAKHZYRO 150 mg every 4 weeks, 300 mg every 4 weeks or 300 mg every 2 weeks in subjects with HAE.
The PK-PD relationship between TAKHZYRO and cHMWK is described by an indirect exposure-response pharmacological model. The cHMWK formation rate was maximally reduced by 53.7% with an IC₅₀ of 5705 ng/ml.
Clinical efficacy and safety: HELP study: The HELP study was a multicenter, randomised, double-blind, placebo-controlled parallel-group study in 125 (115 adults and 10 adolescents) subjects with symptomatic type I or II HAE. Subjects were randomised into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab 150 mg every 4 weeks [q4wks], lanadelumab 300 mg every 4 weeks [q4wks], or lanadelumab 300 mg every 2 weeks [q2wks] by SC injection) for the 26-week treatment period.
The median (range) age of the study population was 42 (12 to 73) years with 88 female subjects (70%). A history of laryngeal angioedema attacks was reported in 65% (81/125) of subjects and 56% (70/125) were on prior long-term prophylaxis (LTP). During the study run-in period, the mean attack rate was 3.7 attacks/month with 52% (65/125) of subjects experiencing ≥3 attacks/month.
All TAKHZYRO treatment arms produced statistically significant reductions in the mean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population (ITT) (Table 1). (See Table 1.)

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The mean reduction in HAE attack rate was consistently higher across the TAKHZYRO treatment arms compared to placebo regardless of the baseline history of LTP, laryngeal attacks, or attack rate during the run-in period. The percentage of subjects who were attack free is provided in Table 2. (See Table 2.)

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The percentage of patients who were attack free for the last 16-weeks (Day 70 to Day 182) of the study was 77% in the 300 mg q2wks group, compared to 3% of patients in the placebo group.
100% of the subjects on 300 mg q2wks or q4wks and 89% on 150 mg q4wks achieved at least a 50% reduction in HAE attack rate compared to the run-in period.
Health related Quality of Life: All TAKHZYRO treatment groups observed an improvement in Angioedema Quality of Life Questionnaire (AE-QoL) total and domain (functioning, fatigue/mood, fear/shame, and nutrition) scores compared to the placebo group; the largest improvement was observed in the functioning score as shown in Table 3. A reduction of 6 points is considered a clinically meaningful improvement. The percentage of patients who achieved a clinically meaningful improvement in AE-QoL total score was 65% (Odds ratio vs placebo, [95% CI]= 3.2 [1.1, 9.2]), 63% (2.9 [1.1, 8.1]), and 81% (7.2 [2.2, 23.4]), in TAKHZYRO 150 mg q4 wks, 300 mg q4 wks, and 300 mg q2 wks groups, respectively, compared to 37% of patients in the placebo group. (See Table 3.)

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HELP study extension: Long-term safety and efficacy of TAKHZYRO for prophylaxis to prevent HAE attacks was evaluated in an open-label HELP study extension.
A total of 212 adult and adolescent subjects with symptomatic type I or II HAE received at least one dose of lanadelumab in this study, including 109 subjects who entered as rollover subjects from the HELP study and 103 new or non-rollover subjects (including 19 subjects from Phase1b study) who had an historical baseline attack rate of ≥1 attack per 12 weeks Subjects were allowed to initiate self-administration after receiving the first 2 doses from a health care professional in clinic and completing appropriate training. Interim analysis indicates that the effect was sustained up to one year of treatment.
Pharmacokinetics: The single and multiple dose pharmacokinetics of lanadelumab have been studied in patients with HAE. Pharmacokinetics of lanadelumab showed linear dose-exposure response with doses up to 400 mg and reproducible exposure following subcutaneous administration up to 12 months. The absolute bioavailability of lanadelumab after subcutaneous administration has not been determined. In the HELP study, patients treated with 300 mg q2 wks presented mean (SD) area under the curve over the dosing interval at steady-state (AUC_tau,ss), maximum concentration at steady-state (C_max,ss) and minimum concentration at steady-state (C_min,ss) of 408 μg*day/ml (138), 34.4 μg/mL (11.2), and 25.4 μg/mL (9.18), respectively. The anticipated time to reach steady state concentration was approximately 70 days.
Absorption: Following SC administration, the time to maximum concentration is approximately 5 days. The site of SC injection (thigh, arm, or abdomen) and self-administration did not affect the absorption of lanadelumab.
Distribution: The mean (SD) volume of distribution of lanadelumab in patients with HAE is 14.5 litres (4.53). Lanadelumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.
Elimination: Lanadelumab has a mean (SD) total body clearance of 0.0297 L/h (0.0124) and a terminal elimination half-life of approximately 14 days.
Special populations: No dedicated studies have been conducted to evaluate the pharmacokinetics of lanadelumab in special patient populations including gender, age, pregnant women or the presence of renal or hepatic impairment.
In a population pharmacokinetic analysis, after correcting for body weight, no influence of gender or age (12 to 75 years) was apparent on the clearance or volume of distribution of lanadelumab. Although body weight was identified as an important covariate describing the variability of clearance, a 300 mg q2wks dose regimen provided sufficient exposure for the indication (see Pharmacodynamics as previously mentioned).
Renal and hepatic impairment: As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of lanadelumab. Accordingly, in a population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 ml/min/1.73 m² [mild, N=98] and 30 to 59 ml/min/1.73m² [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab.
Toxicology: Preclinical safety data: In repeat-dose studies evaluating once weekly SC injection in both rats (up to 28 days) and cynomolgus monkeys (up to 6 months) lanadelumab was well-tolerated at doses of up to and including 50 mg/kg (highest dose tested) with no organs of toxicity identified.
Exposures in cynomolgus monkeys following 6 months of administration were approximately 23-fold greater than that noted at 300 mg q2 wks based on AUC.
Lanadelumab is not expected to interact directly with DNA or other chromosomal material, as it is made up entirely of naturally occurring amino acids and contains no inorganic or synthetic linkers or other nonprotein portions; therefore no genotoxicity evaluation has been conducted.
Carcinogenicity has not been evaluated in animals as based on the weight of evidence approach, lanadelumab is considered to have a low risk for carcinogenicity.
The effects of lanadelumab on fertility were evaluated in sexually mature cynomolgus monkeys. In a 13-week study, once weekly SC administration of lanadelumab had no effects on male or female fertility at doses of 10 or 50 mg/kg (highest dose tested). Exposures in sexually mature cynomolgus monkeys in the fertility study were approximately 20- and 22-fold greater than that noted at 300 mg q2 wks based on C_max and AUC, respectively.
In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo-foetal development, survival, growth, and/or postnatal development of offspring. Exposures in the ePPND study were approximately 32-fold greater than that noted at 300 mg q2 wks based on AUC.

TAKHZYRO is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older.

This medicinal product should be initiated under the supervision of a physician experienced in the management of patients with hereditary angioedema (HAE).
Posology: The recommended starting dose is 300 mg lanadelumab every 2 weeks. In patients who are stably attack free on treatment, a dose reduction of 300 mg lanadelumab every 4 weeks may be considered, especially in patients with low weight.
TAKHZYRO is not intended for treatment of acute HAE attacks (see Precautions).
Missed doses: If a dose of TAKHZYRO is missed, the patient should be instructed to administer the dose as soon as possible ensuring at least 10 days between doses.
Special populations: Elderly: Age is not expected to affect exposure to lanadelumab. No dose adjustment is required for patients above 65 years of age (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No studies have been conducted in patients with hepatic impairment. Hepatic impairment is not expected to affect exposure to lanadelumab. No dose adjustment is required in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No studies have been conducted in patients with severe renal impairment. Renal impairment is not expected to affect exposure to lanadelumab or the safety profile. No dose adjustment is required in patients with renal impairment. (See Pharmacology: Pharmacokinetics under Actions.)
Paediatric population: The safety and efficacy of TAKHZYRO in children aged less than 12 years have not been established. No data are available.
Method of administration: TAKHZYRO is intended for subcutaneous (SC) administration only.
Each TAKHZYRO unit (pre-filled syringe) is intended for single use only (see Special precautions for disposal and other handling under Cautions for Usage).
The injection should be restricted to the recommended injection sites: the abdomen, the thighs, and the upper outer arms (see Pharmacology: Pharmacokinetics under Actions). Rotation of the injection site is recommended.
TAKHZYRO may be self-administered or administered by a caregiver only after training on SC injection technique by a healthcare professional.

No case of overdose has been reported. There is no available information to identify potential signs and symptoms of overdose. If symptoms should occur, symptomatic treatment is recommended. There is no antidote available.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity reactions: Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, administration of TAKHZYRO must be stopped immediately and appropriate treatment must be initiated.
General: TAKHZYRO is not intended for treatment of acute HAE attacks. In case of a breakthrough HAE attack, individualized treatment should be initiated with an approved rescue medication. There are no available clinical data on the use of lanadelumab in HAE patients with normal C1-INH activity.
Interference with coagulation test: Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. None of the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverse events. There were no differences in international normalised ratio (INR) between treatment groups.
Effects on ability to drive and use machines: TAKHZYRO has negligible influence on the ability to drive or use machines.

Pregnancy: There are no or limited data from the use of lanadelumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive or developmental toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of lanadelumab during pregnancy.
Breast-feeding: It is unknown whether lanadelumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed child cannot be excluded during this short period. Afterwards, lanadelumab could be used during breast-feeding if clinically needed.
Fertility: Lanadelumab's effect on fertility has not been evaluated in humans. Lanadelumab had no effect on male or female fertility in cynomolgus monkeys (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The most commonly (52.4%) observed adverse reaction associated with TAKHZYRO was injection site reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Of these ISRs, 97% were of mild intensity, 90% resolved within 1 day after onset with a median duration of 6 minutes.
Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) was observed (1.2%), see Precautions.
Tabulated list of adverse reactions: Table 4 summarises adverse reactions observed in the HELP study that included 84 subjects with HAE, who received at least one dose of TAKHZYRO.
The frequency of adverse reactions listed in Table 4 is defined using 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). (See Table 4.)

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Paediatric population: The safety of TAKHZYRO was evaluated in a subgroup of 23 subjects aged 12 to <18 years old. Results of the subgroup analysis were consistent with overall study results for all subjects.
Immunogenicity: Treatment with lanadelumab has been associated with development of treatment emergent anti-drug antibodies (ADA) in 11.9% (10/84) of subjects. All antibody titres were low. The ADA response was transient in 20% (2/10) of ADA positive subjects. 2.4% (2/84) of lanadelumab-treated subjects tested positive for neutralising antibodies.
The development of ADA including neutralising antibodies against TAKHZYRO did not appear to adversely affect the pharmacokinetic (PK) and pharmacodynamics (PD) profiles or clinical response.
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.

No dedicated drug-drug interaction studies have been conducted. Based on the characteristics of lanadelumab, no pharmacokinetic interactions with co-administered medicinal products is expected.
As expected, concomitant use of the rescue medication C1 esterase inhibitor results in an additive effect on lanadelumab-cHMWK response based on the mechanism of action (MOA) of lanadelumab and C1 esterase inhibitor (see Pharmacology: Pharmacodynamics under Actions).

Special precautions for disposal and other handling: Lanadelumab is provided in single use pre-filled syringes.
Before use, TAKHZYRO solution should be visually inspected for appearance. The solution should be clear or slightly yellow. Solutions that are discoloured or contain particles should not be used.
Avoid vigorous agitation.
Administration steps: After removing the pre-filled syringe from the refrigerator, wait 15-30 minutes before injecting to allow the solution to reach room temperature. Inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm (see Dosage & Administration).
Each pre-filled syringe is for single use only. Discard the pre-filled syringe after injection is completed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
All needles and syringes should be disposed of in a sharps container.
Incompatibilities: Not applicable.

Do not freeze.
Keep the solution (pre-filled syringe) in the outer carton in order to protect from light.
The solution (pre-filled syringe) may be stored below 25°C for a single period of 14 days, but not beyond the expiry date. Do not return TAKHZYRO to refrigerated storage after storage at room temperature.

Instructions for use: STEP 1: Prepare for your injection: a. Gather an alcohol swab, cotton ball/gauze pad, adhesive bandage and a sharps disposal container and place on a clean, flat, surface in a well-lit area. These supplies are not included in the TAKHZYRO packaging.
b. Remove TAKHZYRO from refrigerator, open the carton box and remove the TAKHZYRO pre-filled syringe from the tray.
Do not use the TAKHZYRO pre-filled syringe if the tamper evident seal is open or broken.
Before you prepare your injection, allow the pre-filled syringe to reach room temperature for at least 15 to 30 minutes.
Your medicine is sensitive to warm temperatures. Do not use external heat sources such as hot water to warm your TAKHZYRO pre-filled syringe.
Do not remove the needle cap until you are ready to inject.
c. Wash your hands with soap and water. Dry your hands completely.
d. Check the expiration date on the label.
Do not use TAKHZYRO pre-filled syringe if the expiration date has passed.
e. Visually inspect the TAKHZYRO pre-filled syringe for any damage and make sure the medicine is colourless to slightly yellow.
Do not use product if syringe is damaged - e.g., cracked syringe.
Do not administer if the medicine is discoloured, cloudy or has flakes or particles in it and call your Healthcare Provider.
You might see air bubbles in the TAKHZYRO pre-filled syringe. This is normal and will not affect your dose.
STEP 2: Select and prepare your injection site: a. The TAKHZYRO pre-filled syringe should be injected into your stomach (abdomen), thigh, or the back of the upper arm (the outer area of the upper arm is not recommended if you are injecting yourself).
It is important to rotate injection sites to keep skin healthy. Each new injection should be given at least 3 cm from the last site you used.
Do not inject into an area of your body where the skin is irritated, reddened, bruised, or infected.
The area you choose for injection should be at least 5 cm away from any scars or your belly button (navel).
b. Clean the injection site with an alcohol swab and allow it to dry.
Do not fan or blow on the clean site.
Do not touch this area again before giving your injection.
c. Remove needle cap from the TAKHZYRO pre-filled syringe. Gently pull the needle cap straight off with one hand and firmly hold the middle of the TAKHZYRO pre-filled syringe with the other hand. Throw away the needle cap.
Do not recap your TAKHZYRO pre-filled syringe.
Do not use the TAKHZYRO pre-filled syringe if it has been dropped without the needle cap on or if the needle looks damaged or bent.
Do not touch the needle or allow the needle to touch anything.
STEP 3: Inject TAKHZYRO: a. Grip the TAKHZYRO pre-filled syringe in one hand like a pencil. Avoid touching the needle or pushing on the plunger.
b. With your other hand, gently pinch about 3 cm fold of skin at the cleaned injection site.
c. With one quick, short motion, push needle all the way into skin. Make sure to keep the needle in place.
d. Slowly push the plunger until all of the liquid is injected and the syringe is empty, then gently let go of your skin.
e. Slowly withdraw needle while maintaining the syringe at the same angle.
f. Press cotton ball or gauze pad over injection site if needed and hold for 10 seconds.
Do not rub the injection site. You may have a minor bleeding. This is normal.
Cover injection site with an adhesive bandage if needed.
g. Throw away your used TAKHZYRO pre-filled syringe.
Do not touch the needle.
To avoid a needle-stick injury, do not recap the needle.
Put your used TAKHZYRO pre-filled syringes in a sharps disposal container right away after use.
Do not reuse the TAKHZYRO pre-filled syringe and any of your injection supplies.

Other Cardiovascular Drugs

B06AC05 - lanadelumab ; Belong to the class of drugs used in the treatment of hereditary angioedema.

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