Gonal-F (Emd Serono, A Division of Emd Inc., Canada, 5.5 mcg): Uses, Side Effects and Dosage

What is GONAL-f® used for?

• GONAL-f® is used to to help eggs develop in women as part of Assisted Reproductive Technologies (ART), which are procedures that may help you become pregnant, such as IVF (In Vitro Fertilization). To help eggs develop fully, another hormone called, hCG (human chorionic gonadotropin), is given.

• GONAL-f® is also used to help eggs develop in some patients with irregular or absent menstrual cycles. To complete the development of eggs, another hormone, hCG, is given.

How does GONAL-f® work?

GONAL-f® is a hormone called FSH (follicle stimulating hormone), which belongs to a group of medicines called “gonadotropins”. Gonadotropins are involved in reproduction and fertility.

GONAL-f® is a purified form of FSH that causes eggs to develop in women. GONAL-f® is a highly purified form of FSH that is manufactured using the latest technology with proven effectiveness and safety in clinical studies.

GONAL-f® belongs to a group of medicines called “gonadotropins”.

What are the ingredients in GONAL-f®?

Medicinal ingredients: Follitropin alfa

Non-medicinal ingredients: The non-medicinal ingredients in GONAL-f® 75 IU (5.5mcg) single dose vials are: sucrose, disodium phosphate dihydrate, methionine, Polysorbate 20 and sodium dihydrogen phosphate monohydrate. GONAL-f® may also contain O-phosphoric acid and/or sodium hydroxide used for pH adjustment.

The diluent provided for reconstitution is Sterile Water for Injection, Ph.Eur./USP.

GONAL-f® comes in the following dosage forms:

GONAL-f® is available as a lyophilized powder for reconstitution in vials.

GONAL-f® is available in 75 IU (5.5mcg) single dose vials.

Each box for the single doses contains a vial of medication (white powder), a pre-filled syringe of sterile water for injection, Ph.Eur./USP (liquid) and a needle for mixing and a needle for injection.

Do not use GONAL-f® if:

• You have a high level of FSH in your blood that show your ovaries do not work at all. Your thyroid or adrenal function is not under control.
• You are allergic to recombinant human FSH or any of the ingredients in GONAL-f®. You are currently pregnant or breastfeeding
• You have large ovaries or sacs of fluid within your ovaries (ovarian cysts) not due to polycystic ovarian disease (PCOS)
• You have abnormal bleeding from your uterus or vagina from an unknown cause You have tumours of the ovary, uterus, breast or brain (hypothalamus or pituitary gland)

To help avoid side effects and ensure proper use, talk to your healthcare professional before you take GONAL-f®. Talk about any health conditions or problems you may have, including:

Porphyria

If you have porphyria or someone in your family has porphyria, GONAL-f® may increase the risk of a sudden attack. Tell your healthcare professional immediately if:

• Your skin becomes fragile and easily blistered, especially skin that is in the sun a lot, and/or
• You have stomach, arm or leg pain

In case of the above events your healthcare professional may recommend that you stop treatment.

Overstimulation of the Ovary During FSH Therapy

Ovarian Enlargement

Using FSH therapy help eggs develop can lead to the growth of more than one egg. This may cause your ovaries to be abnormally large. Symptoms of large ovaries include bloating or pain in your lower stomach (pelvic) area. This is more commonly seen in women with polycystic ovarian syndrome (PCOS).

Ovarian Hyperstimulation Syndrome (OHSS)

This treatment increases the chance of a condition called ovarian hyperstimulation syndrome (OHSS). OHSS is a serious medical condition that can happen when your ovaries produce too many eggs (overstimulated). OHSS can cause fluid to suddenly build-up in the area of your stomach and chest areas and can cause blood clots to form. In rare cases, severe OHSS can cause death. OHSS may also happen after you stop using GONAL-F®. Stop using GONAL-F® and call your healthcare professional right away if you have symptoms of OHSS, including: severe swelling of the stomach area, trouble breathing, diarrhea, severe lower stomach (pelvic) area pain, feeling sick (nausea), vomiting, decreased urine output, and weight gain. However, if you are not ovulating, and if the recommended dose and schedule of administration are adhered to, the occurrence of OHSS is less likely. GONAL-f® treatment will hardly ever cause a severe case of OHSS unless another medicine called hCG is given to help the final egg development. If the risk of OHSS exists or OHSS is starting, its best not to get hCG, and women should avoid getting pregnant by not having sex.

Breathing and Blood Clotting

Using gonadotropin can lead to serious breathing problems like collapsing of the lungs, extreme shortness of breath and worsening of asthma.

It may also raise the chance of getting a blood clot, which can cause major health issues like blockage in the lungs, blood vessel problems, heart attack, stroke, or blockage in the arteries in your arms and legs. In rare cases, these problems have led to death.

Reproductive Issues

GONAL-F® may increase your chance of having a pregnancy that is abnormally outside of your womb (ectopic pregnancy). Your chance of having a pregnancy outside of your womb is increased if you also have fallopian tube problems. Call your healthcare provider right away if you have symptoms of an ectopic pregnancy including: stomach or pelvic pain especially on one side, neck pain, nausea and vomiting, shoulder pain, and rectal pain.

Miscarriages may be higher than in the normal population, but comparable with the rates found in women with fertility problems.

When using GONAL-f®, you have a higher risk of being pregnant with more than one child at the same time (“multiple pregnancy”, mostly twins), than if you conceived naturally. The chance of this occurring depends on the schedule of your medication and is similar between GONAL-f® and other drugs like GONAL-f® (gonadotropins). Your healthcare professional will monitor you closely to help minimize the possibility of multiple pregnancy.

In women receiving fertility treatment, tumours (in the ovary) have been reported. It is not known if treatment with fertility medicines increase the chance of a tumour developing in these women.

Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements or alternative medicines.

The following may interact with GONAL-f®:

GONAL-f® is often used with other medicines to help eggs develop. If you’re also taking GONAL-f® at the same time as a “gonadotropin-releasing hormone” (GnRH) agonist or antagonist (these medicines reduce your sex hormone levels and stop you ovulating, your healthcare provider may adjust your GONAL-f® dose. Major interactions with other medicines have not been reported.

How to take GONAL-f®:

How is GONAL-f® administered?

GONAL-f® cannot be taken orally because it would be digested in the stomach and for this reason, it must be taken by injection. Due to its high level of purity, GONAL-f® is approved for subcutaneous injection (just under the skin), which is easier and less painful than intramuscular injections (in the muscle). In fact, with professional guidance, you can learn to inject yourself, in the comfort and privacy of your own home.

How is GONAL-f® different from other treatments?

Over time, the medicines used to treat infertility have improved and changed a lot. . Many other products do not use special technology and contain different amounts of FSH, LH and urinary proteins.

GONAL-f® is made using a special technology called recombinant technology. It consists only of very purified rFSH.

How long will one treatment cycle last?

This depends on the average follicular response to therapy. Every treatment cycle is individualized and your healthcare professional will need to carefully evaluate how you respond.

How to inject GONAL-f®:

The most easily accessible areas for subcutaneous injection are the abdomen and thighs. The absorption of GONAL-f® is the same regardless of the injection site selected. You may find the injection is more comfortable if you vary the site each time you inject GONAL-f®.

Below is a diagram with shaded areas demonstrating the recommended subcutaneous injection sites.

HOW TO INJECT GONAL-f®

A Step by Step Guide

Understandably, you may be a little apprehensive at first about giving yourself an injection. That is why this information has been produced. Refer to it as necessary and follow each instruction step by step. If you have any questions or concerns that are not addressed here, please consult your clinic.

Every treatment is individualized. Yours has been carefully designed for you by your healthcare professional according to your own specific needs. It is very important that you keep your appointments and follow your healthcare professional instructions, particularly with regard to the amount and frequency of the medication you are taking. If you have concerns regarding your dosage, consult your healthcare professional. Do not adjust your dosage without being instructed to do so. If you forget or miss an injection, do not panic, but you should call your healthcare professional for advice.

IMPORTANT POINTS TO REMEMBER

Always follow the basic principles of self injection:

• It is recommended that you inject GONAL-f® at around the same time each day.
• Use a clean work surface and clean skin as directed.
• Always check expiry date before use. Never use expired GONAL-f®.
• Check dosage and instructions for mixing.
• Be sure to use the correct strength and correct amount of diluent.
• Check medication after reconstitution - do not use if medication is cloudy, lumpy or discoloured.
• Alternate injection sites each day.
• Check and record site of injections each day.

If you are unsure about the mixing of the solution, or have difficulty with the injections, call Momentum at 1-800-387-8479 or your clinic immediately.

Please read through the following instructions before you begin, in order to become familiar with self-administration of GONAL-f®. If you have been prescribed GONAL-f® single dose vials, but the diluent is in a vial, please see your clinic for the specific reconstitution steps.

Please note that mcg is pronounced "microgram" and is a unit of measure. 1 gram is equivalent to 1 million micrograms.

1. 1.

   GETTING READY

   • On a clean work surface, lay out everything you will need:

     • GONAL-f® mono-dose vial(s) of white powder
     • Diluent in pre-filled syringe
     • One needle for reconstitution (mixing)
     • One ½ inch, 25, 27 or 29 gauge needle for injection

     • Two alcohol wipes

     • Needle disposal container
   • If you use your kitchen to prepare the injection, ensure that all medicines and needles are kept well away from food. As for the injection itself, it can be given in any room where you feel comfortable.
2. 2.

   CLEANSE

   • Before you start, wash your hands well with soap and water. It is important that your hands and the items you use be as clean as possible.
   • Needles should not touch any surface except inside the vials and alcohol-cleaned skin; keep them capped prior to use.
   • Make sure you use a new needle each time you inject to avoid contamination.
3. 3.

   PREPARE THE PRE-FILLED SYRINGE OF DILUENT

   • Carefully twist off the cap at the tip of the barrel of the pre-filled syringe.
   • Remove the mixing needle from its package, being careful to keep the protective needle cap in place.
   • Carefully twist the mixing needle onto the barrel of the pre-filled syringe until it is tightened.
   • Carefully lay the syringe down on a flat, clean, surface.

Reconstitution Volumes

Volumes used for reconstitution should be between 0.5 and 1.0 mL; up to 225 IU (16.5mcg) may be dissolved in 0.5 ml of diluent (Sterile Water for Injection, USP). Following reconstitution, the medication in the vials should be used immediately, and any unused solution should be discarded.

1. 4.

   MIXING GONAL-f® SINGLE DOSE VIAL(S)

   • You should have a set number of vials, as prescribed by your healthcare professional, containing GONAL-f® (white powder).
   • Using your thumb, flip off the plastic cap of the GONAL-f® vial.
   • Continue to open all vials in this manner, if required.
   • Wipe the rubber stopper on the top of the vial with an alcohol wipe.
   • Carefully twist the needle cap off the pre-filled syringe labelled "Sterile Water for Injection, USP" prepared in previous step 3.
   • Position the needle in a straight, downward position over the marked centre circle of the rubber stopper on the vial of GONAL-f® powder.
   • Keep the needle in a straight, downward position as you insert it through the centre circle or it may be difficult to depress the plunger.
   • Slowly inject the liquid into the vial by pushing the syringe plunger down (volume to be confirmed by your physician). The sterile water and white powder will mix to form a clear liquid.
   • Do not shake the vial. If bubbles appear, wait a few moments for the bubbles to settle.
   • DO NOT USE IF SOLUTION APPEARS CLOUDY, LUMPY or DISCOLOURED. Report this and the lot number to your healthcare professional.
   • When all of the sterile water (diluent) has been injected into the vial, keep the needle in the vial, lift the vial and turn it upside down with the needle pointing toward the ceiling. With the needle tip in the liquid, slowly pull back the plunger until the vial is empty. Be careful not to pull the plunger out of the syringe. Remove the needle from the vial.
   • If you have been prescribed more than one vial of GONAL-f®, repeat the points above using the mixed solution in the syringe to dissolve the next vial. Continue in the same manner until you have the prescribed number of powder vials dissolved in the solution.
   • Discard empty vials in the needle disposal container.
2. 5.

   REMOVE AIR BUBBLES AND CHANGE NEEDLE

   • Hold the syringe with the needle pointing upwards and gently flick the syringe if there are any visible air bubbles. The air bubbles will collect at the top of the syringe. If there are no air bubbles, or if there is no air space at the top of the syringe, pull the plunger back to allow an air space.
   • Recap the needle and twist to remove; replace with the ½ inch, 25, 27 or 29 gauge injection needle with cap. Lay syringe down on the clean surface.
   • Do not worry if you are unable to remove very tiny bubbles; they will do no harm. When you invert the syringe, the air space will be next to the plunger. This space will ensure that all of the medication has been injected. The air will remain in the needle.
3. 6.

   PREPARE THE INJECTION SITE

   • Select the site of injection (e.g. top of thigh, tummy).
   • Wipe the chosen area with an alcohol wipe, cleansing an area of approximately 5 cm x 5 cm.
   • Lay the used side of the wipe next to your working surface or on the alcohol wipe wrapper.
4. 7.

   INJECTING THE SOLUTION

   • Pick up the syringe and remove the cap from the needle.
   • Invert the needle and hold as if throwing a dart.
   • With your other hand, gently squeeze the skin together to make a little elevation at the injection site.
   • Using a "dart like motion", insert the needle at a 90-degree angle (You need very little force but quick action).
   • Once the needle is inserted into the tissue all the way, inject the solution by pushing gently on the plunger with your thumb of the hand holding the syringe. Take as much time as you need to inject all the solution.
   • Immediately withdraw the needle and clean the site with the clean side of the alcohol swab using a circular motion. If there is minor oozing you may need to apply a small amount of pressure for a minute.
5. 8.

   DISPOSE OF ALL USED ITEMS

   • Once you have finished your injection, immediately discard the needles and syringe (without recapping the needle) into the disposal container.
   • Take the container to a clinic or pharmacy for proper disposal when the needle disposal container is full or when you have completed your entire treatment.

Usual dose:

Every treatment is individualized. Your treatment has been carefully designed for you by your healthcare professional. Over the course of your treatment, doses may range between 75 to 450 IU depending on your specific medical condition and your response to the medicine.

Overdose:

Missed dose:

Do not take a double dose to make up for any doses you have missed. Contact your healthcare professional for advice if you forget to take a dose of GONAL-f®.

What are possible side effects from using GONAL-f®?

These are not all the possible side effects you may have when taking GONAL-f®. If you experience any side effects not listed here, tell your healthcare professional.

Fertility drugs are safe to take with close monitoring by your doctor. As with all medication, there is a potential for side effects.

The following side effects have been reported with the use of GONAL-f® during clinical trials and post-market use:

Common and Very Common: may affect 1 to 10 users in 100

• Ovarian cysts
• Mild to moderate ovarian enlargement
• Breast tenderness
• Mild to moderate OHSS
• Mild to severe injection site reaction (such as pain, redness, bruising, swelling and/or irritation)
• Headache
• Stomach pain or bloating
• Feeling sick (nausea), vomiting, diarrhea

Uncommon, Rare and Very Rare: may affect less than 1 to 10 users in 1,000

• Severe OHSS
• Blood clots (thrombosis)
• Difficulty breathing (acute pulmonary distress)
• Worsening of asthma
• Mild to severe allergic reactions (hypersensitivity) such as rash, red skin, hives, swelling of your face with difficulty breathing may occur. These reactions can sometimes be serious.

The greatest concern your healthcare professional will have is ovarian hyperstimulation syndrome (OHSS). To avoid the development of OHSS, your healthcare professional will carefully monitor your response to GONAL-f®. Ovarian enlargement, sometimes accompanied by abdominal bloating and pain, may occur in about 20% of women taking gonadotropins. This is generally reversed with cessation of treatment and severe life-threatening cases are rare.

A causal relationship between treatment with fertility drugs and ovarian cancer has not been established.

The following medical events have been reported subsequent to pregnancies resulting from gonadotropin therapy in controlled clinical trials: spontaneous abortion, tubal pregnancy, premature labour, postpartum fever and congenital abnormalities.

None of these events were thought to be drug-related. The incidence is not more than that found in the general population.

Reporting Side Effects

Storage:

GONAL-f® vials of lyophilized powder are stable when stored at or below room temperature (25 ^oC) and protected from light.

Do not freeze.

Do not use the product after the expiry date indicated on the label.

Keep out of reach and sight of children.

Reconstituted Product

Check medication after reconstitution - do not use if medication is cloudy, lumpy or discoloured.

Following reconstitution, the medication in the vials should be used immediately, and any unused solution should be discarded.

If you want more information about GONAL-f®:

• Talk to your healthcare professional
• Find the full product monograph that is prepared for healthcare professionals and includes this Patient Medication Information by visiting the Health Canada website: (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html; http://www.emdserono.ca, or by calling 1-800-387-8479.

GONAL-f® is a trademark of Merck KGaA, Darmstadt, Germany or its affiliates.

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