Firazyr

Get emergency medical help if you have any of these signs of an allergic reaction after using icatibant:

• chest pain or discomfort, fast or weak heartbeat;
• flushing (warmth, redness, or tingly feeling);
• feeling like you might pass out;
• itching, rash, or hives;
• runny nose, sneezing, stuffy nose;
• wheezing, cough, throat irritation, trouble breathing; or
• swelling of your face, lips, tongue, or throat.

An allergic reaction to icatibant can cause symptoms that are very similar to the signs of hereditary angioedema.

Less serious side effects may include:

• dizziness, drowsiness, tired feeling;
• nausea, vomiting, diarrhea;
• fever;
• headache;
• mild skin rash; or
• pain, pressure, swelling, bruising, burning, warmth, redness, numbness, tenderness, itching, rash, or other irritation where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Shire Orphan Therapies, Inc.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include redness, itching, or feeling like you might pass out.

Get emergency medical help if you have any of these signs of an allergic reaction after using icatibant:

• chest pain or discomfort, fast or weak heartbeat;

• flushing (warmth, redness, or tingly feeling);

• feeling like you might pass out;

• itching, rash, or hives;

• runny nose, sneezing, stuffy nose;

• wheezing, cough, throat irritation, trouble breathing; or

• swelling of your face, lips, tongue, or throat.

An allergic reaction to icatibant can cause symptoms that are very similar to the signs of hereditary angioedema.

Less serious side effects may include:

• dizziness, drowsiness, tired feeling;

• nausea, vomiting, diarrhea;

• fever;

• headache;

• mild skin rash; or

• pain, pressure, swelling, bruising, burning, warmth, redness, numbness, tenderness, itching, rash, or other irritation where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Synthetic decapeptide similar in structure to bradykinin; a selective bradykinin type 2 (B2) receptor antagonist.1 2 5

Hereditary Angioedema

Treatment of acute attacks of hereditary angioedema (HAE);1 2 6 21 designated an orphan drug by FDA for this use.9

Currently not FDA-labeled or recommended for prophylaxis of HAE attacks.1 13

• Advise patients of maximum dosage; do not administer >3 doses of 30 mg each (total of 90 mg) within a 24-hour period.1

• Advise patients to immediately seek medical attention after treating a laryngeal HAE attack with icatibant.1

• Risk of injection site reactions.1 Importance of patients informing clinicians if any erythema, bruising, swelling, warmth, burning sensation, pruritus, irritation, urticaria, numbness, pressure, or pain occurs at injection site.1

• Risk of pyrexia, elevated serum aminotransferases (ALT, AST), and rash.1

• Risk of fatigue, drowsiness, and dizziness; do not perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) if such symptoms occur.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Icatibant injection is used to treat sudden attacks of hereditary angioedema (HAE). Icatibant works by blocking a chemical in the body that causes swelling, inflammation, and pain for patients with HAE. This medicine is not a cure for HAE.

This medicine is available only with your doctor's prescription.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Irritation where the shot is given.
• Dizziness.
• Upset stomach.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Firazyr or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Firazyr. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Firazyr® (icatibant) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Icatibant was not teratogenic in rats or rabbits; however, it caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits. Firazyr should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Delayed parturition and fetal death in rats occurred at 0.5 and 2-fold, respectively, the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively). Increased pre-implantation loss in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). In rabbits, premature birth and abortion rates increased at a dose that was less than 1/40th the MRHD (on a mg/m2 basis at a maternal dose of 0.1 mg/kg). Studies in rabbits also indicated that pre-implantation loss and increased fetal deaths occurred at 13-fold greater than the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

Nonteratogenic effects: Impairment of pup air-righting reflex and decreased pup hair growth in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

Labor and Delivery

There are no human studies that have investigated the effects of Firazyr on preterm labor or labor at term; however, animal studies showed that icatibant causes delayed parturition and associated fetal death in rats and premature birth and abortion in rabbits. Delayed parturition occurred in rats at 0.5-fold times the MRHD (on an AUC basis at a maternal dose of 1 mg/kg).

Nursing Mothers

Because many drugs are excreted in human milk, caution should be exercised when Firazyr is administered to a nursing woman. Icatibant is excreted into the milk of lactating rats.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Juvenile Toxicity Data

Subcutaneous daily administration of icatibant to young rats during the juvenile period of development (postnatal days 22-70) delayed the sexual maturation of male reproductive tissues (atrophy of testes and epididymides) at exposures approximating one-third or greater the MRHD on a mg/m2 basis. Impaired fertility and reproductive performance were also observed in male rats at the end of the postnatal treatment period at exposures approximating the MRHD or greater on a mg/m2 basis. No effects were observed in females at exposures approximating 3-fold the MRHD on a mg/m2 basis. The observed tissue findings in males were consistent with those seen in sexually mature rats and dogs and are attributed to antagonism of the bradykinin B2 receptor and subsequent effects on gonadotropins. The observed effects may be a consequence of daily icatibant administration. Toxicity to the testis did not occur in dogs treated twice a week for 9 months [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

Geriatric Use

Clinical studies of Firazyr did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients are likely to have increased systemic exposure to Firazyr compared to younger (18-45 years) patients [see Clinical Pharmacology (12.3)]. Since other reported clinical experience has not identified differences in efficacy and safety between elderly and younger patients, no dose adjustment is recommended.

Hepatic Impairment

Firazyr was studied in patients with mild to moderate (Child Pugh scores of 5 to 8) hepatic impairment. No change in systemic exposure is noted in these patient populations. No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Renal Impairment

Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with Firazyr had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min. Firazyr is cleared non-renally and hence it is not expected to show any change in systemic exposure in patients with impaired renal function. No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year studies were conducted in CD1 mice and Wistar rats to assess the carcinogenic potential of Firazyr. 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 Maximum Recommended Human Dose 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 degenenerate 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.

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. Firazyr 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.

How Supplied

Firazyr 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.

Firazyr is available in cartons containing one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-02.

Firazyr 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 54092-702-03.

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.

You should not use Firazyr if you are allergic to icatibant.

To make sure you can safely use Firazyr, tell your doctor about all of your medical conditions.

FDA pregnancy category C. It is not known whether Firazyr will harm an unborn baby. Tell your doctor if you are pregnant before using this medication. It is not known whether icatibant passes into breast milk or if it could harm a nursing baby. Do not use Firazyr without telling your doctor if you are breast-feeding a baby.

Animal studies have revealed preimplantation loss, abortion, fetal death, premature birth, and delayed parturition. There are no controlled data in human pregnancy. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus. AU TGA pregnancy category: C US FDA pregnancy category: C