Zypadhera 300 mg powder and solvent for prolonged-release injectable suspension

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

ZYPADHERA 210 mg powder and solvent for prolonged-release injectable suspension

ZYPADHERA 300 mg powder and solvent for prolonged-release injectable suspension

ZYPADHERA 405 mg powder and solvent for prolonged-release injectable suspension

Olanzapine

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.

• If you have any questions, consult your doctor or nurse.

• If you experience any adverse reactions, consult your doctor or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Contents of the leaflet:

1. What ZYPADHERA is and what it is used for

2. What you need to know before using ZYPADHERA

3. How to use ZYPADHERA

4. Possible side effects

5. How to store ZYPADHERA

6. Contents of the pack and other information

1. What ZYPADHERA is and what it is used for

ZYPADHERA contains olanzapine as the active substance. ZYPADHERA belongs to a group of medicines called antipsychotics and is used to treat schizophrenia – a condition with symptoms such as hearing, seeing, or perceiving things that do not exist, false beliefs, unusual suspiciousness, and social withdrawal. People with this illness may also feel depressed, anxious, or tense.

ZYPADHERA is indicated for use in adult patients who have been previously stabilized on oral olanzapine treatment.

2. What you need to know before using ZYPADHERA

Do not use ZYPADHERA:

• if you are allergic to olanzapine or to any of the other ingredients of this medicine (listed in section 6). An allergic reaction may present as skin rash, itching, swelling of the face or lips, or difficulty breathing. If you have ever experienced any of these symptoms, please inform your doctor or nurse.
• if you have previously been diagnosed with eye problems, such as certain types of glaucoma (increased pressure in the eye).

Warnings and precautions

Talk to your doctor or nurse before starting to use ZYPADHERA.

• A rare but serious reaction may occur after each injection. Sometimes, ZYPADHERA may enter the bloodstream too quickly. If this happens, you may experience one or more of the symptoms listed below after each injection. In some cases, these symptoms may lead to loss of consciousness.

These symptoms usually disappear within 24 to 72 hours after the injection. After each injection, you must remain under observation at your healthcare facility for at least 3 hours in case any of the above-mentioned symptoms occur.

Although unlikely, you may experience these symptoms more than 3 hours after the injection. If this happens, contact your doctor or nurse immediately. Because of this risk, you must not drive or operate machinery for the remainder of the day after each injection.

• If you feel dizzy or faint after the injection, inform your doctor or nurse. You may need to lie down until you feel better. Your doctor or nurse may want to check your blood pressure and pulse.

• The use of ZYPADHERA is not recommended in elderly patients with dementia (confusion or memory loss), as it may cause serious adverse effects.

• Very rarely, medicines of this type can cause unusual movements, mainly of the face or tongue, or a combination of fever, rapid breathing, sweating, muscle stiffness, and drowsiness or lethargy. If this occurs after receiving ZYPADHERA, inform your doctor or nurse immediately.

• Weight gain has been observed in patients taking ZYPADHERA. You and your doctor should monitor your weight regularly. If necessary, your doctor may help you plan a diet or consider referring you to a nutritionist.

• Elevated levels of blood sugar and fats (triglycerides and cholesterol) have been observed in patients using ZYPADHERA. Your doctor should perform blood tests to monitor your blood sugar and fat levels before starting ZYPADHERA and regularly during treatment.

• Inform your doctor if you or a family member has a history of blood clots, as medicines of this type have been associated with blood clot formation.

Inform your doctor as soon as possible if you suffer from any of the following conditions:

• Stroke or "mini" stroke (transient ischemic attack)
• Parkinson's disease
• Prostate problems
• Intestinal obstruction (paralytic ileus)
• Liver or kidney disease
• Blood disorders
• Recent heart attack, coronary artery disease, sick sinus syndrome (abnormal heart rhythms), unstable angina, or low blood pressure
• Diabetes
• Seizures
• If you think you may have salt loss due to prolonged severe diarrhea and vomiting, or from using diuretic medicines (water tablets)

As a routine precaution, periodic blood pressure monitoring is recommended in patients over 65 years of age.

Initiating treatment with ZYPADHERA is not recommended if you are over 75 years old.

Children and adolescents

Patients under 18 years of age must not use ZYPADHERA.

Other medicines and ZYPADHERA

Inform your doctor if you are taking, have recently taken, or might need to take any other medicines.

In particular, inform your doctor if you are taking:

• Medicines for Parkinson's disease.
• Carbamazepine (an antiepileptic and mood stabilizer), fluvoxamine (an antidepressant), or ciprofloxacin (an antibiotic) – your ZYPADHERA dose may need to be adjusted.

If you are already taking antidepressants, medicines for anxiety, or medicines to help you sleep (tranquilizers), you may feel more drowsy when taking ZYPADHERA.

Use of ZYPADHERA with alcohol

You must avoid all alcohol consumption if you have been administered ZYPADHERA, as it may cause drowsiness when combined with alcohol.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you might be pregnant, or plan to become pregnant, consult your doctor before receiving this injection.

You must not receive this injection if you are breastfeeding, as small amounts of olanzapine may pass into breast milk.

The following symptoms may occur in newborn babies of mothers who have been treated with ZYPADHERA during the last trimester of pregnancy (last three months of pregnancy): tremors, muscle stiffness and/or weakness, drowsiness, agitation, breathing difficulties, and feeding problems. If your baby develops any of these symptoms, contact your doctor.

Driving and use of machines

Do not drive or operate machinery for the remainder of the day after each injection.

ZYPADHERA contains sodium

Once reconstituted, this medicine contains less than 1 mmol of sodium (23 mg) per vial; this is essentially “sodium-free”.

3. How to use ZYPADHERA

Your doctor will decide the amount of ZYPADHERA you need and how often you should receive an injection. ZYPADHERA is administered at doses of 150 mg to 300 mg every 2 weeks or 300 mg to 405 mg every 4 weeks.

ZYPADHERA is supplied as a powder which your doctor or nurse will reconstitute to form a suspension that will then be injected into the muscle of your buttock.

If you use more ZYPADHERA than you should

This medicine will be administered under medical supervision. Therefore, it is unlikely that you will receive an excessive amount.

Patients who have received more olanzapine than they should have experienced the following symptoms:

• Fast heartbeat, agitation/aggression, speech disorders, unusual movements (especially in the face or tongue), and decreased levels of consciousness.

Other possible symptoms may include:

• Acute confusion, seizures (epilepsy), coma, a combination of fever, rapid breathing, sweating, muscle stiffness, and a state of drowsiness or lethargy, slowed breathing, aspiration, high or low blood pressure, and abnormal heart rhythms.

Contact your doctor or hospital immediately if you experience any of the symptoms described above.

If you forget to use ZYPADHERA

Do not stop your treatment just because you start feeling better. It is important that you continue receiving ZYPADHERA for the entire duration prescribed by your doctor.

If you miss your appointment for an injection, you should contact your doctor to schedule the next injection as soon as possible.

If you have any further questions about the use of this medicine, ask your doctor or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Contact your doctor immediately if you have:

• excessive drowsiness, dizziness, confusion, disorientation, difficulty speaking, difficulty walking, muscle stiffness or agitation, weakness, irritability, aggressiveness, anxiety, increased blood pressure, or seizures, which may even lead to loss of consciousness. These signs and symptoms may be due to ZYPADHERA sometimes entering the bloodstream too quickly (a common adverse effect affecting up to 1 in 10 people);
• unusual movements (a common adverse effect affecting up to 1 in 10 people), especially of the face or tongue;
• blood clots in the veins (an uncommon adverse effect affecting up to 1 in 100 people), particularly in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through the bloodstream to the lungs, causing chest pain and difficulty breathing. If you experience any of these symptoms, seek medical attention immediately.
• a combination of fever, rapid breathing, sweating, muscle stiffness, and mental confusion or drowsiness (frequency cannot be estimated from available data).

Other common adverse effects (may affect up to 1 in 10 people) with ZYPADHERA include drowsiness and injection site pain.

Rare adverse effects with ZYPADHERA (may affect up to 1 in 1,000 people) include infection at the injection site.

The adverse effects listed below have been observed with oral olanzapine, but may also occur following administration of ZYPADHERA.

Other very common adverse effects (may affect more than 1 in 10 people) include weight gain and increased blood prolactin levels. In the early stages of treatment, some people may experience dizziness or fainting (with slower heartbeats), particularly when standing up from lying or sitting positions. This sensation usually resolves spontaneously, but if it does not, consult your doctor.

Other common adverse effects (may affect up to 1 in 10 people) include changes in levels of certain blood cells, blood fats, and transient increases in liver enzymes at the beginning of treatment; increased blood and urine sugar levels; increased levels of uric acid and creatine phosphokinase in blood; increased appetite; dizziness; agitation; tremor; unusual movements (dyskinesias); constipation; dry mouth; skin rash; loss of strength; excessive fatigue; fluid retention causing swelling of the hands, ankles, or feet; fever; joint pain; and sexual dysfunction such as decreased libido in men and women or erectile dysfunction in men.

Other uncommon adverse effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling of the mouth and throat, itching; skin rash); diabetes or worsening of diabetes, occasionally associated with ketoacidosis (acetone in blood and urine) or coma; seizures, which in most cases are related to a history of seizures (epilepsy); muscle stiffness or spasms (including eye movements); restless legs syndrome; speech problems; stuttering; slow heart rate; sensitivity to sunlight; nosebleeds; abdominal distension; excessive salivation; memory loss or forgetfulness; urinary incontinence; inability to urinate; hair loss; absence or reduced menstrual periods; and changes in the breast gland in men and women such as abnormal milk production or abnormal growth.

Rare adverse effects (may affect up to 1 in 1,000 people) include decreased normal body temperature; abnormal heart rhythms; sudden death of unknown origin; inflammation of the pancreas causing severe stomach pain; fever and vomiting; liver disease manifesting as yellowing of the skin and whites of the eyes; muscle disease manifesting with joint pains of unknown origin; and prolonged and/or painful erection.

Very rare adverse effects include severe allergic reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS). Initially, DRESS presents with flu-like symptoms and a rash on the face, followed by widespread rash, fever, enlarged lymph nodes, elevated liver enzymes seen in blood tests, and an increase in a type of white blood cells (eosinophilia).

During treatment with olanzapine, elderly patients with dementia may experience stroke, pneumonia, urinary incontinence, falls, excessive fatigue, visual hallucinations, increased body temperature, skin redness, and difficulty walking. Some fatal cases have been observed in this particular group of patients.

Oral olanzapine may worsen symptoms in patients with Parkinson's disease.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. ZYPADHERA Storage

Keep this medicine out of the sight and reach of children.

Do not administer the injection after the expiry date stated on the container.

Do not refrigerate or freeze.

Chemical and physical stability of the suspension in the vials has been demonstrated for 24 hours at 20 - 25°C. From a microbiological standpoint, the medicine should be administered immediately. If this is not the case, the storage times and conditions of use prior to administration are the responsibility of the healthcare professional and should normally not exceed 24 hours at 20 - 25°C. Do not use this product if you notice discolouration or any other visible signs of deterioration.

If the medicine is not used immediately, it must be shaken vigorously to achieve resuspension. Once the suspension has been withdrawn from the vial into the syringe, it must be used immediately.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of ZYPADHERA

The active substance is olanzapine.

ZYPADHERA 210 mg: Each vial contains olanzapine pamoate monohydrate, equivalent to 210 mg of olanzapine.

ZYPADHERA 300 mg: Each vial contains olanzapine pamoate monohydrate, equivalent to 300 mg of olanzapine.

ZYPADHERA 405 mg: Each vial contains olanzapine pamoate monohydrate, equivalent to 405 mg of olanzapine.

After reconstitution, each milliliter of suspension contains 150 mg/mL of olanzapine.

The components of the solvent are sodium carmellose, mannitol, polysorbate 80, water for injections, hydrochloric acid, and sodium hydroxide.

Appearance of the product and contents of the pack

ZYPADHERA prolonged-release injectable suspension is supplied as a yellow powder in a clear glass vial. Your doctor or nurse will reconstitute it into a suspension for administration by injection, using the contents of the ZYPADHERA solvent vial, which is a clear, colourless or pale yellow solution, contained in a clear glass vial.

ZYPADHERA is a powder and solvent for prolonged-release injectable suspension. Each pack contains one vial of powder for prolonged-release injectable suspension, one 3 mL solvent vial, one syringe with an attached 19-gauge, 38 mm safety needle, and three separate safety needles: one 19-gauge, 38 mm needle and two 19-gauge, 50 mm needles.

Marketing Authorisation Holder

CHEPLAPHARM Registration GmbH, Weilerstr. 5e, 79540 Lörrach, Germany.

Manufacturer

Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain.

Manufacturing Packaging Farmaca (MPF) B.V., Neptunus 12, 8448 CN Heerenveen, The Netherlands.

CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.

CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 23-24, 17489 Greifswald, Germany.

Date of the most recent revision of this leaflet:

Detailed information about this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu/.

INSTRUCTIONS FOR HEALTHCARE PROFESSIONALS

INSTRUCTIONS FOR RECONSTITUTION AND ADMINISTRATION

ZYPADHERA olanzapine powder and solvent for prolonged-release injectable suspension

FOR DEEP INTRAMUSCULAR INJECTION IN THE GLUTEAL MUSCLE ONLY.

DO NOT ADMINISTER BY INTRAVENOUS OR SUBCUTANEOUS ROUTE.

Reconstitution

STEP 1: Preparation of materials

The pack contains:

• Vial of ZYPADHERA powder for prolonged-release injectable suspension
• Vial of ZYPADHERA solvent
• One hypodermic syringe and one safety needle (hypodermic device)
• One 19-gauge, 38 mm hypodermic safety needle
• Two 19-gauge, 50 mm hypodermic safety needles
• Package leaflet
• Reconstitution and Administration Instructions Card (this document)
• Safety and Instructions for Use of the Hypodermic Device Information

It is recommended to use gloves since ZYPADHERA may cause skin irritation.

Reconstitute ZYPADHERA prolonged-release injectable suspension powder exclusively with the solvent supplied in the package, using standard aseptic techniques for reconstitution of parenteral products.

STEP 2: Determination of solvent volume for reconstitution

This table indicates the amount of solvent required to reconstitute ZYPADHERA prolonged-release injectable suspension powder.

It is important to emphasize that the vial contains more solvent than necessary to reconstitute the product.

STEP 3: Reconstitution of ZYPADHERA

1. Gently tap the vial to loosen the powder.

2. Open the hypodermic syringe and the needle pre-packaged with the needle protection device. Open the plastic bag and remove the device. Attach the syringe (if not already connected) to the Luer connector of the device with a simple twist. Securely place the needle onto the device by pushing and turning clockwise. Then, directly remove the needle cap. Failure to follow these instructions may result in a needle-stick injury.

3. Withdraw the predetermined volume of solvent (Step 2) into the syringe.

4. Inject the required volume of solvent into the vial of powder.

5. Withdraw air to equalize pressure in the vial.

6. Remove the needle, holding the vial upright to prevent loss of solvent.

7. Engage the needle safety device. Place the needle into its sheath using a one-handed technique. Perform this maneuver with one hand by applying GENTLE pressure to the sheath against a flat surface. WHEN PRESSING ON THE SHEATH (Fig. 1), THE NEEDLE SECURELY ATTACHES TO IT (Fig. 2).

8. Visually confirm that the needle is completely attached to its protective sheath. Remove the device with the needle attached to the syringe, when required, using a specific medical procedure. Remove it by holding the Luer connector of the needle protection device with the thumb and index finger, keeping the other three fingers away from the area where the needle tip is located (Fig. 3).

1. Strike the vial vigorously several times against a hard surface until no visible powder remains. Protect the surface to cushion the impact. (See Figure A)

Figure A: Shake vigorously to mix

1. Visually inspect the vial for clumping of the powder. Powder not in suspension appears as dry, pale yellow lumps adhering to the vial. Continue shaking if lumps remain. (See Figure B)

Without suspension: visible clumps
Suspended: no clumps

Figure B: Check for unsuspended powder and continue tapping if necessary.

1. Shake the vial vigorously until the suspension appears uniform with homogeneous color and texture. The suspended product will appear yellow and opaque. (See Figure C)

Figure C: Shake the vial vigorously

If foam forms, allow the vial to stand until the foam dissipates. If the product is not used immediately, it must be shaken vigorously to achieve resuspension. Reconstituted ZYPADHERA remains stable in the vial for up to 24 hours.

Administration

STEP 1: Inject ZYPADHERA

This table confirms the final volume of ZYPADHERA suspension to be injected. The concentration of the suspension is 150 mg/mL of olanzapine.

1. Determine which needle to use for administering the injection to the patient. For obese patients, 50 mm needles are recommended for injection:
   • If using the 50 mm needle for injection, attach the 38 mm safety needle to the syringe to withdraw the required volume of suspension.
   • If using the 38 mm needle for injection, attach the 50 mm safety needle to withdraw the required volume of suspension.
2. Slowly withdraw the desired amount. A small amount of product will remain in the vial.
3. Attach the needle safety device and remove the needle from the syringe.
4. Attach the safety needle—selecting either the 50 mm or the 38 mm—to the syringe before injection. Once the suspension has been withdrawn from the vial into the syringe, it must be injected immediately.
5. Select and prepare the injection site in the gluteal area. DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY.
6. After inserting the needle, aspirate for a few seconds to confirm that no blood appears. If blood is aspirated into the syringe, discard the syringe and prepare a new suspension. The injection should be administered with firm and continuous pressure.

DO NOT MASSAGE THE INJECTION SITE.

1. Engage the needle safety device. (Fig. 1 and 2)
2. Dispose of vials, used syringes, used needles, extra needle, and any remaining solvent according to appropriate clinical procedures. The vial is for single use only.