SAJAZIR (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year studies were conducted in CD1 mice and Wistar rats to assess the carcinogenic potential of icatibant. No evidence of tumorigenicity was observed in mice and rats at icatibant subcutaneous doses up to 15 mg/kg/day (twice per week) and 6 mg/kg/day (daily), respectively (approximately 10-fold and 6-fold greater than the MRHD on an AUC basis, respectively).

Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test.

Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis).

In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week.

Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up to 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively.

13.2 Animal Toxicology and/or Pharmacology

The B2 receptor has been implicated in the cardioprotective effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects during reperfusion after acute ischemia. Icatibant decreased coronary blood flow in the isolated guinea pig heart and aggravated the duration of post-ischemic reperfusion arrhythmias in the isolated rat heart. Intracoronary infusion of icatibant in an anesthetized myocardial infarction dog model increased mortality rate 2-fold over saline ischemia. There is limited human experience in acute ischemia. Icatibant injection should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient.

14 CLINICAL STUDIES

The efficacy and safety of icatibant injection for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling.

Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either icatibant injection 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label icatibant injection 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-item VAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant injection (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p<0.001).

Figure 2 Time to 50% reduction from baseline in 3-item VAS score.

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Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for icatibant injection and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with icatibant injection used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo.

In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received icatibant injection 30 mg for the treatment of an acute HAE attack. Across the three trials, icatibant injection had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours.

Recurrent attacks

In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with icatibant injection 30 mg and could receive up to 3 doses of icatibant injection 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg icatibant injection for 987 attacks of acute HAE in these trials. In an assessment of the first 5 icatibant injection-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of icatibant injection.

Laryngeal attacks

A total of 60 patients with laryngeal attacks were treated with icatibant injection in the controlled trials. Efficacy results were similar to those observed for non-laryngeal (cutaneous and abdominal) sites of attack.

Self-administration

Self-administration of icatibant injection by 56 patients was assessed in an open label trial. Patients who administered icatibant injection during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

SAJAZIR (icatibant) injection is supplied as a single-use, prefilled syringe for subcutaneous administration. Each syringe delivers 3 mL of a sterile solution of icatibant 30 mg (as icatibant acetate). Each glass syringe has a bromobutyl plunger stopper, which is not made of latex natural rubber.

SAJAZIR is available in cartons containing one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 70709-013-01.

SAJAZIR is also available in a pack containing 3 cartons; each carton contains one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 70709-013-03.

16.2 Storage and Handling

Keep out of the reach of children.

Store between 2 — 25° C (36 — 77° F).

Do not freeze.

Store in carton until time of administration.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

17.1 Information for Patients

Patients may self-administer SAJAZIR upon recognition of an HAE attack after training under the guidance of a healthcare professional.

Patients with laryngeal symptoms should seek medical attention immediately in an appropriate healthcare facility after administration of SAJAZIR [see Warnings and Precautions (5.1)].

Injection site reactions are reported in most patients after administration of SAJAZIR. Other adverse reactions reported after administration of SAJAZIR include pyrexia, increase in transaminases, dizziness, and rash [see Adverse Reactions (6.1)].

Tiredness, drowsiness, and dizziness have been reported following the use of SAJAZIR. Patients should be advised not to drive or use machinery if they feel tired or dizzy.

Manufactured by:

Cipla Ltd., India

At M/s. Gland Pharma Limited, India

Manufactured for:

Cycle Pharmaceuticals Ltd

The Broers Building

21 JJ Thomson Ave

Cambridge, CB3 0FA, United Kingdom

Revised: 06/2021

Patient Information

SAJAZIR™ (Sah ja’ zeer)

(icatibant) Injection

Please read this Patient Information before you use SAJAZIR™ Injection and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is SAJAZIR?

SAJAZIR is a medicine used to treat acute attacks of hereditary angioedema (HAE) in adults 18 years and older. It is not known if SAJAZIR is safe or effective for children under 18 years of age.

What should I tell my healthcare provider before taking SAJAZIR?

Before you use, SAJAZIR tell your healthcare provider if you:

  • have any other medical conditions.
  • are breastfeeding or plan to breastfeed. It is not known if SAJAZIR passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use SAJAZIR .
  • are pregnant or plan to become pregnant. It is not known if SAJAZIR will harm your unborn baby. You and your healthcare provider will decide if SAJAZIR is right for you.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

How should I use SAJAZIR?

  • Use SAJAZIR exactly as your healthcare provider tells you to use it.
  • Your healthcare provider will prescribe the right dose of SAJAZIR for you and tell you when to use it.
  • Your healthcare provider will teach you or a caregiver how to give SAJAZIR.
  • Read the Instructions for Use at the end of the Patient Information for information about the right way to use SAJAZIR.
  • If your symptoms continue or come back, you may repeat your SAJAZIR at least six hours apart.
  • Do not use more than 3 doses in 24 hours.
  • If you have a laryngeal attack , inject SAJAZIR and then go to the nearest hospital emergency room right away.

What should I avoid while using SAJAZIR?

Tiredness, drowsiness, and dizziness can occur in people who take SAJAZIR. If this occurs, do not drive a car, use machinery, or do anything that needs you to be alert.

What are the possible side effects of SAJAZIR?

The most common side effects of SAJAZIR include:

  • redness, bruising, swelling, warmth, burning, itching, irritation, hives, numbness, pressure, or pain at the injection site
  • fever
  • too much of an enzyme called transaminase in your blood
  • dizziness
  • nausea
  • headache
  • rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of SAJAZIR. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SAJAZIR?

  • Store SAJAZIR between 36˚F to 77˚F (2˚C to 25˚C).
  • Do not freeze.
  • Store SAJAZIR in the original carton until you are ready to use it.

Keep SAJAZIR and all medicines out of the reach of children.

General information about the safe and effective use of SAJAZIR

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SAJAZIR for a condition for which it was not prescribed. Do not give SAJAZIR to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about SAJAZIR. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SAJAZIR that is written for health professionals.

For more information, call 1-800-836-4380.

What are the ingredients in SAJAZIR?

Active ingredient: icatibant acetate

Inactive Ingredients: sodium chloride, glacial acetic acid, sodium hydroxide, and water

Step-by-Step Instructions for your SAJAZIR

Step 1. Preparing your dose of SAJAZIR

  • Wash your hands with soap and water.
  • You will need the following supplies:
  • Your SAJAZIR carton that includes 1 single-use SAJAZIR prefilled syringe and 1 needle.
  • An alcohol wipe
  • The medicine inside your SAJAZIR prefilled syringe should be clear and colorless. Do not use your SAJAZIR prefilled syringe if the solution contains particles, is cloudy, or an unusual color.
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Figure A

Step 2. Remove the prefilled syringe and needle from the carton. See Figure B.

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(click image for full-size original)

Figure B

Step 3. Remove the seal from the needle cap (the needle should remain inside the protective needle cap until ready to use). See Figure C.

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Figure C

Step 4. Remove the protective cap from the end of the pre-filled syringe by unscrewing the cap. Hold the syringe firmly. Carefully attach the needle to the prefilled syringe containing the colorless Icatibant Injection solution. See Figure D.

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Figure D

Step 5. Firmly screw the needle on the prefilled syringe. Be careful not to remove the needle from the needle cap. See Figure E.

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Figure E

Preparing the Injection Site

Step 6. Choose the injection site. The injection site should be a fold of skin on your stomach, about 2 to 4 inches (5 to 10 cm) below your belly button on either side. See Figure F.

The area you choose for injection should be at least 2 inches (5 cm) away from any scars. Do not choose an area that is bruised, swollen, or painful.

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Figure F

Step 7. Clean your SAJAZIR site with an alcohol wipe and allow it to dry. See Figure G.

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Figure G

Injecting your SAJAZIR

Step 8. Remove the needle from the needle cap by holding the needle cap and carefully pulling the syringe. Do not pull up on the plunger. See Figure H.

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Figure H

Step 9. Hold the SAJAZIR prefilled syringe in 1 hand, between your fingers and thumb. See Figure I.

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Figure I

Step 10. Use your other hand to gently pinch the fold of skin you cleaned with the alcohol wipe between your thumb and fingers for your injection. See Figure J.

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Figure J

Step 11. Hold the syringe between a 45 to 90 degree angle to your skin with the needle facing the fold of skin you are holding. See Figure K.

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(click image for full-size original)

Figure K

Step 12. Hold the fold of skin. Bring the syringe to the skin and quickly insert the needle into the skin fold. See Figure L.

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Figure L

Step 13. Push the plunger, at the top of the syringe, over at least 30 seconds until no SAJAZIR is in the syringe. See Figure M.

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Figure M

Step 14. Release the skin fold and gently pull the needle out. See Figure N.

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Figure N

Disposal of your used SAJAZIR prefilled syringe

Step 15. Place the used SAJAZIR syringe, with the needle attached, in a sharps container (such as a red biohazard container), a hard plastic container, (such as a detergent bottle), or a metal container (such as an empty coffee can). Seal the container and throw it away the right way. There may be state and local laws about the right way to throw away used syringes and needles. Ask your healthcare provider or pharmacist how to throw away used syringes and needles. See Figure O.

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Figure O

This Patient Package Insert and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Manufactured by:

Cipla Ltd., India

At M/s. Gland Pharma Limited, India

Manufactured for:

Cycle Pharmaceuticals Ltd

The Broers Building

21 JJ Thomson Ave

Cambridge, CB3 0FA, United Kingdom

Revised: 04/2021

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