Active ingredients: Botulinum toxin type A
BOTOX® 100 Allergan Units, Powder for solution for injection
BOTOX® 200 Allergan Units, Powder for solution for injection
Why is Botox used? What is it for?
What is BOTOX
BOTOX is a muscle relaxant drug that is injected into the muscles, bladder wall or under the skin. It works by partially blocking nerve impulses in each muscle where it is injected and reduces excessive contractions of these muscles.
When BOTOX is injected under the skin, it acts on the sweat glands to reduce the amount of sweat produced.
When injected into the bladder wall, BOTOX acts on the bladder musculature to reduce urine loss (urinary incontinence). In the case of chronic migraine, BOTOX is believed to be able to block pain signals, which indirectly block the development of migraine. However, how BOTOX works in chronic migraine has not been fully understood.
What is BOTOX for
In adults, BOTOX is used to control:
- persistent muscle spasms in the eyelids and face
- persistent muscle spasms in the neck and shoulders
- persistent muscle spasms in the wrist and hand in stroke patients
- excessive sweating of the armpits which interferes with normal daily activities when other local treatments are not helpful
- overactive bladder with urinary incontinence - sudden urge to empty the bladder and the need to go to the bathroom more frequently than normal - when other drugs (called anticholinergics) have not helped
- urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis.
BOTOX is used to reduce the symptoms of chronic migraine in adults:
- with headache for 15 days or more per month of which at least 8 days with migraine and who have not had an adequate response or are intolerant to anti-migraine drugs given for prophylaxis.
Chronic migraine is a disease that affects the nervous system. Usually patients suffer from pain in the head often accompanied by excessive sensitivity to light, loud sounds or scents / smells, as well as nausea and / or vomiting. head occur for 15 days or more per month BOTOX has been shown to significantly reduce symptoms and improve the quality of life of patients suffering from chronic migraine.
BOTOX should only be prescribed for you if you have been diagnosed with chronic migraine by a neurologist who specializes in this field. BOTOX should be administered under the supervision of a neurologist. BOTOX is not used for acute migraine, chronic tension-type headaches or in patients with drug overuse headaches.
In children aged 2 years and over with cerebral palsy who are unable to walk, BOTOX is used to control:
- foot deformity caused by persistent leg muscle spasms. BOTOX relieves persistent muscle spasms in the legs.
Contraindications When Botox should not be used
Do not use BOTOX
- if you are allergic (hypersensitive) to botulinum toxin type A or to any of the other ingredients of BOTOX;
- if you have a proposed "injection site infection";
- if you are being treated for urinary incontinence and develop a "urinary tract infection or experience" sudden inability to empty your bladder (and do not regularly use a catheter);
- if you are being treated for urinary incontinence and do not intend to use a catheter if necessary.
Take special care with BOTOX
Before using BOTOX
Tell your doctor if:
- have had problems with injections in the past (such as fainting);
- you have inflammation in the muscles or in the area of the skin where the doctor intends to inject;
- have significant weakness or loss of muscle tone where your doctor intends to inject;
- have ever had problems with swallowing or with food or liquids accidentally coming into contact with the lungs, especially if you are being treated for persistent muscle spasms in the neck and shoulders;
- suffer from any other muscle problems or chronic diseases affecting the muscles (such as myasthenia gravis or Eaton Lambert syndrome);
- suffer from certain diseases of the nervous system (such as amyotrophic lateral sclerosis or motor neuropathy);
- have an eye disease called closed-angle glaucoma (high pressure in the eye) or have been told that you are at risk of developing this type of glaucoma;
- have had any operation or injury that may have changed the muscle to be injected in any way;
- is being treated for overactive bladder with urinary incontinence and is a man who has signs and symptoms of urinary obstruction, such as difficulty passing urine or weak or intermittent flow
After being treated with BOTOX
Contact your doctor and get immediate attention if the following happen:
- difficulty breathing, swallowing, or the ability to speak;
- hives, swelling including swelling of the face or throat, wheezing, feeling faint and short of breath (possible symptoms of a severe allergic reaction).
Precautions for use What you need to know before taking Botox
If you are treated with BOTOX too often or the dose is too high, your body may start producing antibodies which can reduce the effect of BOTOX.
If you have not practiced a lot of physical activity for a long time before receiving BOTOX treatment, any activity should be gradually resumed after the treatments.
This medicine is unlikely to improve the degree of movement in the joints where the surrounding muscle has lost its ability to stretch.
When BOTOX is used in the treatment of persistent eyelid muscle spasms, it can decrease blinking and damage the surface of the eyes. To prevent this, treatment with eye drops, ophthalmic ointments, soft contact lenses or even protective devices may be required. which ones to protect the eye. Your doctor will tell you if this is necessary.
When using BOTOX to control urine loss, your doctor will need to give you antibiotics before and after treatment to prevent any urinary tract infections.
Your doctor will see you about 2 weeks after the injection if you have not used a catheter before the injection. You will be asked to urinate there and the total volume of urine remaining in the bladder will then be measured by ultrasound. Your doctor will decide if you need to come back for the same test during the next 12 weeks. Talk to your doctor if you are unable to urinate at any time, as you may need to start using a catheter. In patients with urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis, approximately one third of those who did not use a catheter prior to treatment may need to use a catheter after treatment. In patients with urinary incontinence due to overactive bladder, approximately 6 in 100 patients may need to use a catheter after treatment.
Interactions What drugs or foods can modify the effect of Botox
Tell your doctor or pharmacist if:
- are taking antibiotics (used to treat infections), anticholinesterase drugs, heart rhythm drugs or muscle relaxants. Some of these medicines may increase the effect of BOTOX.
- you have recently received treatment with a medicine containing botulinum toxin (the active ingredient in BOTOX) as this can greatly increase the effect of BOTOX.
- uses any antiplatelet agent (products similar to aspirin) and / or anticoagulants (blood thinners).
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
Pregnancy and breastfeeding
BOTOX should not be used during pregnancy and in women of childbearing potential who are not using contraceptives, unless clearly needed. Ask your doctor for advice if you are pregnant, planning to become pregnant or become pregnant during treatment. Your doctor will discuss with you whether you should continue the treatment.
BOTOX is not recommended for lactating women.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
BOTOX can cause dizziness, sleepiness, fatigue or vision problems. If you have experienced any of these effects, do not drive or use machines. If you are unsure, ask your doctor for advice.
Dose, Method and Time of Administration How to use Botox: Posology
BOTOX should only be injected by doctors with specific skills on how to use the medicine.
Method and route of administration
BOTOX is injected into the muscles (intramuscularly), into the bladder wall using a specific instrument (cystoscope) for injection into the bladder or into the skin (intradermally). It is injected directly into the affected area; your doctor will usually inject BOTOX into several sites within each affected area.
General information on dosage
- The number of injections per muscle and the dose vary according to the indications. However, your doctor will decide how much, how often and into which muscle (s) to inject BOTOX. It is recommended that the physician use the lowest effective dose.
- Dosages for the elderly are the same as those for adults.
The dosage of BOTOX and the duration of its effect vary according to the disorder for which you are being treated. Details of each disorder are given below.
The safety and efficacy of BOTOX in the treatment of persistent muscle spasms of the eyelid, face, neck and shoulders in children (under 12 years of age) have not been demonstrated. The safety and efficacy of BOTOX in the treatment of chronic migraine in children (under 18 years) have not been studied.
The safety and efficacy of BOTOX in the treatment of excessive armpit sweating have not been studied in children under 12 years of age. Experience with the use of BOTOX in the treatment of excessive armpit sweating in adolescents between 12 and 17 years of age is very limited.
The efficacy of BOTOX in this age group has not been confirmed. For more information, contact your doctor.
The safety and efficacy of BOTOX in the treatment of stroke associated upper limb spasticity have not been established in children and adolescents below 18 years of age.
The safety and efficacy of BOTOX in the treatment of urinary incontinence in pediatric patients less than 18 years of age have not been established.
For persistent muscle spasms of the eyelid and face
Dosage
In the first treatment session, the doctor may perform multiple injections into the affected muscles of 1.25 to 2.5 Units of BOTOX at each injection site.
The maximum dose for the first treatment session is 25 Units per affected area (e.g. per eye). For subsequent treatment sessions, the maximum total dose can be increased up to 100 Units if necessary.
Duration of the treatment effect
You will usually see improvement within 3 days after the injection. The maximum effect is usually noticed 1 to 2 weeks after treatment.
When the effect starts to disappear, the treatment can be repeated if necessary, but not more often than every 3 months.
For persistent muscle spasms of the neck and shoulders
Dosage
The doctor can perform multiple injections into the affected muscles up to 50 Units of BOTOX for each injection site.
The maximum dose for the first treatment session is 200 Units. For subsequent treatment sessions, the maximum dose can be increased up to 300 Units.
Duration of the treatment effect
You will usually see improvement within 2 weeks after the injection.
The maximum effect is usually noticed about 6 weeks after treatment.
When the effect begins to wear off, the treatment can be repeated if necessary, but not more often than every 10 weeks.
For persistent muscle spasms of the wrist and hands in stroke patients
Dosage
The doctor can perform multiple injections into the affected muscles. The dose and number of injections vary based on a number of factors, including your needs, the muscles to be treated, the size of the muscles, the severity of the spasms, etc.
Duration of the treatment effect
You will usually see improvement within the first 2 weeks after the injection.
The maximum effect is usually noticed between 4 and 6 weeks after treatment.
When the effect begins to wear off, the treatment can be repeated if necessary, but not more often than every 12 weeks.
For excessive sweating of the armpits
Dosage
Your doctor may give BOTOX injections to multiple sites in the axillary area. The total dose per armpit is 50 Units of BOTOX.
Duration of the treatment effect
You will usually see improvement within the first week after the injection.
The effect usually lasts an average of 7.5 months after the first injection and about 1 in 4 patients still show the treatment effect after one year.
When the effect begins to wear off, the treatment can be repeated if necessary, but not more often than every 16 weeks.
For persistent leg muscle spasms in children with cerebral palsy
Dosage
The doctor can perform multiple injections into the affected muscles. The dose will depend on the weight of the child.
Duration of the treatment effect
You will usually see improvement within the first 2 weeks after the injection.
When the effect starts to disappear, it is possible to repeat a subsequent treatment, but not more often than every 3 months. The doctor can find a dose that justifies the treatments up to 6 months apart.
For urinary incontinence due to overactive bladder
Dosage
The doctor will perform multiple injections into the bladder wall. The total dose is 100 Units of BOTOX. You may be given a local anesthetic before the injections (your bladder will be filled with anesthetic solution for a while and then emptied.) You may also be given a sedative.
You will have to wait 30 minutes after the treatment to see if you are able to urinate spontaneously.
Duration of the treatment effect
There is usually improvement within the first 2 weeks of injections.
Generally the effect lasts 5 - 6 months after injection.
If the effects start to wear off, you can go back to the treatment if needed, but not more often than every 3 months.
For urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis
Dosage
The doctor will perform multiple injections into the bladder wall. The total dose is 200 units of BOTOX. You may be given a local or general anesthetic before the injections. You may also be given a sedative.
Duration of the therapeutic effect
You will usually see improvement within 2 weeks of the injection.
Generally the effect lasts 8-10 months after injection.
When the effects begin to wear off, you can go back to the treatment if needed, but not more often than every 3 months.
For the treatment of headache in adults suffering from chronic migraine
Dosage
Your doctor may give multiple injections into certain muscles of the face, head and neck with up to 5 units of BOTOX at each injection site. Injections should be spread over 7 specific muscle areas of the head / neck with half the number of injections given on the left and half on the right side of the head and neck.
The total dosage range is between 155 and 195 units per treatment session.
Duration of the treatment effect
When the effect starts to disappear, the treatment can be repeated, but not more often than every 12 weeks.
Overdose What to do if you have taken too much Botox
Signs of BOTOX overdose may not appear for several days after injection. If you have swallowed BOTOX or accidentally injected it, you should contact your doctor who can monitor you for several weeks.
If you have received an overdose of BOTOX, you may have some of the following symptoms and if so contact your doctor immediately who will decide whether to go to hospital:
- difficulty breathing, swallowing or speaking due to muscle paralysis;
- food or liquids accidentally coming into contact with the lungs which can cause pneumonia (infection of the lungs) due to muscle paralysis;
- drooping of the eyelids, double vision;
- general weakness.
If you have any further questions on the use of BOTOX, ask your doctor or pharmacist.
Side Effects What are the side effects of Botox
Like all medicines, BOTOX can cause side effects, although not everybody gets them.
In general, side effects occur within the first few days after treatment. These usually last only for a short time but can last for several months and, in rare cases, even longer.
IF YOU HAVE ANY DIFFICULTY IN BREATHING, SWALLOWING OR SPEAKING AFTER RECEIVING A BOTOX TREATMENT, CONTACT YOUR DOCTOR IMMEDIATELY.
If you experience hives, swelling including swelling of the face or throat, wheezing, feeling faint and short of breath, contact your doctor immediately.
Side effects are classified into the following categories, depending on how often they occur:
Listed below are the side effects which vary depending on the part of the body where BOTOX is injected:
Injections in the eyelid and face
Very common side effect:
- drooping of the eyelid.
Common side effects:
- swelling of the face;
- localized corneal damage (clear surface covering the front of the eye);
- difficulty closing the eye completely;
- excessive tearing;
- irritation;
- dry eye, eye irritation and sensitivity to light;
- bruises under the skin.
Uncommon side effects:
- dizziness;
- vision disturbances;
- blurred vision;
- double vision;
- tiredness;
- inflammation of the cornea (clear surface covering the front of the eye);
- weakness of the facial muscles;
- relaxation of the muscles of one side of the face;
- rash;
- abnormal inward or outward movement of the eyelids.
Rare side effect:
- swelling of the eyelid.
Very rare side effects:
- ulcer, damage to the cornea (clear surface covering the front of the eye);
- high pressure in the eye.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections in the neck and shoulder
Very common side effects:
- difficulty in swallowing;
- ache;
- muscle weakness.
Common side effects:
- dizziness;
- flu syndrome;
- drowsiness
- muscle cramps;
- reduced skin sensitivity;
- feeling of weakness;
- feeling of general malaise;
- feeling nauseous;
- headache;
- stiffness or soreness of the muscles;
- swelling and irritation of the upper airways (rhinitis);
- nasal congestion or runny nose, cough, sore throat, tickling or irritation of the throat;
- dry mouth.
Uncommon side effects:
- shortness of breath;
- double vision;
- fever;
- drooping of the eyelid;
- change of voice.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections in the wrist and hand in stroke patients
Common side effects:
- muscle weakness;
- increased muscle tension;
- bruising and bleeding under the skin causing red areas (bruising or purpura);
- bleeding or burning at the injection site;
- pain in the hands and fingers;
- pain where the injection is given;
- fever;
- flu syndrome.
Uncommon side effects:
- depression;
- decrease in blood pressure on standing which causes dizziness, lightheadedness or fainting;
- feeling of dizziness or 'spinning' (vertigo);
- lack of coordination of movements;
- memory loss;
- generalized weakness;
- ache;
- joint pain or inflammation;
- reduced skin sensitivity;
- numbness or tingling;
- swelling of the extremities such as hands and feet;
- inflammation of the skin (dermatitis);
- headache;
- feeling of general malaise;
- feeling nauseous;
- increased sensitivity at the injection site;
- rash;
- numbness or tingling around the mouth;
- difficulty sleeping (insomnia);
- itch.
Some of these uncommon side effects may also be related to your disease.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections for excessive sweating of the armpits
Very common side effects:
- pain at the injection site.
Common side effects:
- pain at the injection site;
- headache;
- numbness or tingling;
- hot flashes;
- increased sweating elsewhere other than the armpit;
- abnormal skin odor;
- itch;
- hair loss;
- swelling under the skin;
- pain in extremities, such as hands and fingers;
- ache;
- reactions and swelling, bleeding or burning and increased sensitivity at the injection site.
Uncommon side effects:
- muscle weakness;
- feeling of weakness;
- muscular pain;
- joint problems;
- feeling nauseous.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Leg injections in children with cerebral palsy
Very common side effects:
- viral infection;
- ear infection.
Common side effects:
- drowsiness;
- muscle weakness;
- pain in extremities, such as the hands and fingers;
- problems in gait;
- numbness or tingling;
- muscular pain;
- urinary incontinence (inability to control bladder emptying);
- feeling of general malaise;
- falls;
- rash;
- pain at the injection site;
- feeling of weakness.
There have been rare reports of death after BOTOX treatment sometimes associated with aspiration pneumonia in children with cerebral palsy.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections into the bladder wall for urinary incontinence due to overactive bladder
Very common side effects:
- urinary tract infections;
- painful urination after injection *.
Common side effects:
- bacteria in the urine, white blood cells in the urine;
- inability to empty the bladder (urinary retention);
- incomplete emptying of the bladder;
- frequent urination during the day;
- blood in the urine after injection **.
* This side effect may also be related to the injection procedure. ** This side effect is only related to the injection procedure
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections into the bladder wall for urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis
Very common side effects:
- urinary tract infections;
- inability to empty the bladder (urinary retention).
Common side effects:
- difficulty falling asleep (insomnia);
- constipation;
- muscle weakness;
- muscle spasm;
- blood in the urine after injections *;
- painful urination after injections *;
- swelling in the bladder wall (bladder diverticulum);
- tiredness;
- problems with walking (gait disturbances);
- possible uncontrolled reflex reaction of the body (such as profuse sweating, throbbing headache or increased pulse) approximately in conjunction with the injections (autonomic dysreflexia) *;
- falls.
* Some of these common side effects may also be related to the injection procedure.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Injections in the head and neck for the treatment of headache in patients suffering from chronic migraine
Common side effects:
- headache;
- migraine;
- rash;
- itch;
- pain at the injection site;
- neck pain;
- weakness of the facial muscles;
- drooping of the eyelid;
- muscle weakness;
- muscular pain;
- muscle spasm;
- muscle soreness;
- muscle stiffness.
Uncommon side effects:
- difficulty swallowing;
- skin pain;
- pain in the jaw;
- swelling of the eyelids.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
General information about other side effects
Undesirable effects related to the spread of BOTOX distant from the injection site have been reported very rarely and include:
- muscle weakness;
- constipation;
- difficulty swallowing;
- accidental passage of food or fluids into the lungs which in some cases can cause pneumonia.
Difficulty swallowing can range from mild to severe and in some cases requires treatment. In rare cases, people have died due to difficulty swallowing.
Cardiac side effects have been reported rarely:
- irregular heartbeat;
- heart attacks.
Some of these people have passed away. However, some of these patients already had heart problems.
Severe or immediate allergic reactions have been reported rarely, including:
- urticaria;
- swelling including swelling of the face or throat;
- rattle;
- feeling faint;
- shortness of breath.
Cases of
- fits or convulsions after BOTOX treatment, particularly in patients who have previously experienced these symptoms. These effects mainly occurred when BOTOX was used to treat persistent leg muscle spasms in children with cerebral palsy.
As with any injection, side effects related to the inoculum may be reported:
- pain, bruising, bleeding, or infection at the injection site;
- numbness or tingling;
- decreased skin sensitivity;
- soreness;
- swelling / swelling;
- erythema (redness);
- heat of the blood pressure and fainting caused by pain and / or the "anxiety of" needle. After the BOTOX injection, patients also had:
- fever and flu-like symptoms.
The following list lists additional undesirable effects reported with the use of BOTOX, used for any medical condition, since it was marketed:
- allergic reaction;
- loss of innervation to / contraction of the injected muscle;
- breathing difficulties and / or respiratory failure;
- aspiration pneumonia (lung inflammation caused by accidental aspiration of food, drink, saliva or vomit);
- chronic muscle disease (myasthenia gravis);
- blurred vision;
- difficulty seeing clearly;
- strabismus;
- fainting;
- pain / numbness / or weakness starting in the spine;
- fall of the muscles affecting a part of the face;
- weakness of the muscles of the face;
- difficulty moving the arms and shoulders;
- reduced skin sensitivity;
- muscular pain;
- abdominal pain;
- diarrhea, vomiting, loss of appetite;
- fever;
- different types of red patchy rashes;
- feeling of general malaise;
- trouble speaking;
- itch;
- excessive sweating;
- hair loss;
- decreased hearing;
- ringing in the ear;
- feeling of dizziness or 'spinning' (vertigo);
- numbness or tingling.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep BOTOX out of the reach and sight of children.
Your doctor should not use BOTOX after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C - 8 ° C), or in a freezer (-5 ° C or below).
After reconstitution, immediate use of the solution is recommended; however, the product can be stored for up to 24 hours in a refrigerator (2 ° C - 8 ° C).
Composition and pharmaceutical form
What BOTOX contains
- The active ingredient is: Clostridium botulinum botulinum toxin type A. Each vial contains 50, 100 or 200 Allergan Units of Botulinum Toxin type A.
- The other ingredients are human albumin and sodium chloride.
Description of the appearance of BOTOX and contents of the package
BOTOX comes as a white powder in a clear glass vial. Before injection, the product must be reconstituted in a sterile solution for injection of sodium chloride 9 mg / ml (0.9%).
The packs can be of 1, 2, 3 and 6 vials. In addition, BOTOX 50 and 100 Allergan Units of Botulinum Toxin type A is also present in packs of 10 vials.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
BOTOX 100 UNITS ALLERGAN POWDER FOR INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Botulinum toxin * type A, 100 Allergan units per vial.
* from Clostridium botulinum
Botulinum toxin units are not interchangeable from one product to another.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for injection.
White powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
BOTOX is indicated for the treatment:
• blepharospasm, hemifacial spasm and associated focal dystonias;
• cervical dystonia (spasmodic torticollis);
• focal spasticity:
- associated with dynamic clubfoot deformity due to spasticity in walking pediatric patients with cerebral palsy, aged two years or older;
- of the wrist and hand in adult patients with stroke.
• Persistent and severe primary hyperhidrosis of the armpits which interferes with normal daily activities and is resistant to topical treatment.
• Urinary incontinence in adult patients with neurogenic overactivity of the detrusor muscle of the bladder caused by stabilized lesion of the spinal cord starting from the cervical region down to the lower levels or with multiple sclerosis.
• Symptomatic relief in adult patients who meet the diagnostic criteria for chronic migraine (headaches lasting ≥15 days per month including at least 8 days with migraine) and who have shown an insufficient response or are intolerant to migraine prophylaxis drugs ( see section 4.4).
04.2 Posology and method of administration
Dosage
Please refer to the specific recommendations for each indication described below.
Botulinum toxin units are not interchangeable from one product to another. Recommended doses in Allergan units differ from those of other botulinum toxin preparations.
The following information is important: If packs with different strengths of BOTOX are used during the same treatment, take special care to use the right amount of diluent to reconstitute the specific number of units per 0.1ml. The amount of diluent varies between BOTOX 50 Allergan Units, BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe must be properly labeled.
BOTOX should only be reconstituted with sterile sodium chloride 9 mg / ml (0.9%) solution for injection. The right amount of diluent must be drawn with a syringe (see dilution table below).
Dilution instructions for 100 unit vials for urinary incontinence due to neurogenic overactivity of the detrusor muscle of the bladder:
• Reconstitute two 100 unit vials of BOTOX with 6 ml of 0.9% unpreserved saline and mix the vial gently.
• Withdraw 4 ml from each vial using two different 10 ml syringes.
• Withdraw the remaining 2 ml from each vial using a third 10 ml syringe.
• complete the reconstitution by adding 6 ml of preservative-free 0.9% saline to each of the three 10 ml syringes and mix gently.
You will get three 10 ml syringes containing a total of 200 units of reconstituted BOTOX.
Use immediately after reconstitution in syringe. Discard any unused saline.
Dilution table for the BOTOX 100 Allergan Unit pack for all other indications:
This product is for single use only and any unused residual solution should be discarded.
For instructions on the use, handling and disposal of the vials, see section 6.6.
Elderly patients
Adequate dosing studies have not been performed in elderly patients. It is recommended that the lowest effective dose be administered with the longest clinically appropriate interval between treatments. Use particular caution in elderly patients with a significant history and treated concomitantly with other medications.
Pediatric population
The safety and efficacy of BOTOX in the treatment of blepharospasm, hemifacial spasm or cervical dystonia have not been demonstrated in children (less than 12 years of age).
The safety and efficacy of BOTOX in the treatment of urinary incontinence due to neurogenic detrusor overactivity have not been established in the pediatric population (population less than 18 years of age).
The safety and efficacy of BOTOX in the treatment of chronic migraine have not been studied in the pediatric population (population below 18 years of age).
The safety and efficacy of BOTOX in the treatment of primary hyperhidrosis of the armpits have not been studied in children less than 12 years of age. The safety and efficacy of BOTOX in adolescents between 12 and 17 years of age in the treatment of severe axillary hyperhidrosis have not been established.Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made (see sections 4.8 and 5.1).
The safety and efficacy of BOTOX in the treatment of upper limb spasticity associated with stroke have not been established in children and adolescents below 18 years of age.
Method of administration
Please refer to the specific recommendation for each indication described below.
BOTOX should only be administered by appropriately qualified physicians with experience in handling and using the required equipment.
Optimal levels of general validity have not been established for all indications for dosing and the number of injection sites in each muscle. In these cases, individual treatment regimens should be established by the physician. Optimal levels for the Dosage should be determined by titration but the maximum recommended dose should not be exceeded.
Blepharospasm / hemifacial spasm
Reconstituted BOTOX should be injected using a sterile 27-30 gauge / 0.40-0.30 mm needle. Electromyography guidance is not required. The recommended starting dose is between 1.25-2.5 Units to be injected into the medial and lateral region of the orbicularis muscle of the upper eyelid and the lateral region of the orbicularis muscle of the lower eyelid. Additional sites may be injected into the eyebrow area, the lateral orbicular muscle region, and the upper face if spasms in these areas interfere with vision. Avoiding injections near the levator upper eyelid muscle may reduce the possibility to induce ptosis Avoiding injections in the medial part of the lower eyelid, thus decreasing the diffusion in the inferior oblique muscle, can reduce the complication of diplopia.
In general, the initial effect of the injections is observed within three days and reaches its maximum 1-2 weeks after treatment. Each treatment lasts approximately three months, after which the procedure can be repeated as needed. In subsequent sessions, the dose may be be increased up to twice as much if response to initial treatment is considered insufficient. However, there appears to be little benefit from elevating the dose beyond 5 Units per site. The starting dose should not exceed 25 Units per eye. Normally no further benefit is obtained by treating more frequently than once every three months.
In the treatment of blepharospasm the total dose should not exceed 100 Units over the 12 week period.
Patients with hemifacial spasm or seventh nerve disorders should be treated in the same way as those with unilateral blepharospasm, with other affected facial muscles injected as needed.
Cervical dystonia
Reconstituted BOTOX should be injected using an appropriately sized needle (typically 25 - 30 gauge / 0.50 - 0.30 mm).
In clinical trials, the treatment of cervical dystonia typically consisted of an injection of BOTOX into the sternocleidomastoid, levator scapula, scalene, splenium of the head, semispinal, very long and / or trapezius muscle (s). This list is not exhaustive. as all the muscles responsible for controlling the position of the head may be involved and therefore require treatment.
The mass and degree of muscle hypertrophy or atrophy are factors that must be taken into consideration when choosing the appropriate dose. Patterns of muscle activation can spontaneously change in cervical dystonia without a change in the clinical manifestation of dystonia.
In case of difficulty in isolating the single muscles, the injections must be carried out with electromyographic guidance. In the first controlled clinical trials to determine the safety and efficacy of the product for the treatment of cervical dystonia, the doses of reconstituted BOTOX ranged from 140 to 280 Units. In more recent studies, the doses administered ranged from 95 to 360 Units. (on average about 240 Units.) As with any other drug, the starting dosage in an untreated patient should be the lowest effective dose. No more than 50 Units should be administered at each site. No more than 100 Units should be injected into the sternocleidomastoid muscle To minimize the incidence of dysphagia, the sternocleidomastoid should not be injected bilaterally. No more than 200 Units in total should be injected in the first cycle of therapy, making appropriate dose adjustments in subsequent cycles based on the initial response.
The total dose of 300 Units per single session should not be exceeded. The optimal number of injection sites depends on the size of the muscle.
Clinical improvement is generally seen within the first two weeks after injection. Maximum clinical benefit generally occurs approximately six weeks after injection. Intervals in treatment of less than 10 weeks duration are not recommended. The duration of the beneficial effect in clinical studies showed substantial variability (from 2 to 33 weeks) with a typical duration of approximately 12 weeks.
Infantile cerebral palsy
Reconstituted BOTOX should be injected with a sterile 23-26 gauge / 0.60 - 0.45 mm needle. The product is administered as a divided dose by single injections into the medial and lateral tops of the affected gastrocnemius muscle. In hemiplegia, the recommended initial total dose is 4 Units / kg body weight in the affected limb. In diplegia, the initial recommended total dose is 6 Units / kg of body weight divided between the affected limbs. The total dose should not exceed 200 Units.
Clinical improvement usually occurs within the first two weeks after injection.
Further doses should be given when the clinical effect of the previous injection decreases, but not more frequently than once every three months. The dosage regimen can be adjusted to achieve an interval of at least six months between subsequent courses of treatment.
Focal spasticity of the upper limb associated with stroke
Reconstituted BOTOX should be injected with a sterile 25, 27 or 30 gauge needle for superficial muscles and a longer needle for deeper muscles. For the localization of the affected muscles it may be useful to use electromyographic guidance techniques or nerve stimulation. Multiple injection sites ensure more uniform contact of BOTOX with the innervation areas of the muscle and are especially useful in the case of larger muscles.
The correct posology and the number of injection sites must be adapted to individual needs based on the size, number and location of the muscles involved, the severity of the spasticity, any local muscle weakness and the patient's response to a previous treatment.
The following are the doses administered in controlled clinical trials:
In controlled and uncontrolled open label clinical trials, doses between 200 and 240 Units divided among selected muscles were used at a certain course of treatment.
In controlled clinical trials, patients were followed up for 12 weeks after a single treatment.
Improvements in muscle tone were seen within 2 weeks and the greatest effect was generally seen within 4-6 weeks.
In an ongoing uncontrolled open study, most patients were retreated after an interval of 12-16 weeks when the effect on muscle tone was diminishing.
These patients received up to 4 inoculations with a maximum cumulative dose of 960 Units over 54 weeks. If the physician deems it appropriate, repeated doses may be given when the effect of the previous injection is diminishing. Retreatment should not be done before 12 weeks. The degree and type of muscle spasticity present at the time of rhinoculation may make it necessary a dosage adjustment of BOTOX and a variation of the muscles to be treated.
The lowest effective dose should be used.
Primary hyperhidrosis of the armpits
Reconstituted BOTOX (100 Units / 4 mL) is injected using a 30 gauge needle.
50 Units of BOTOX are inoculated intradermally, distributed equally in multiple sites approximately 1-2 cm "from each other, in the hyperhidrosis area of each armpit.
The hyperhidrosis area can be defined using standard staining techniques, such as the Minor starch-iodate test. Doses greater than 50 Units per armpit cannot be recommended.
Clinical improvement generally occurs within the first week of inoculation.
BOTOX can be re-inoculated when the clinical effect of the previous injection diminishes and when the treating physician deems it necessary. Inoculations should not be repeated more often than every 16 weeks (see section 5.1).
Urinary incontinence due to neurogenic overactivity of the bladder detrusor
Patients should not have any urinary tract infections at the time of treatment.
Antibiotics should be given for prophylaxis 1-3 days before treatment, on the day of treatment and 1-3 days after treatment.
It is recommended that patients discontinue antiplatelet therapy at least 3 days prior to the injection procedure. Patients on anticoagulant therapy must be appropriately managed to reduce the risk of bleeding.
Before the injection it is possible to perform an intravesical instillation of diluted anesthetic (with or without sedation) or to proceed to a general anesthesia, according to the local practice of the operating health facility. If a local instillation of anesthetic is performed, the bladder must be emptied and washed with sterile saline before the next steps of the injection procedure.
The recommended dose is 200 units of BOTOX, i.e. 1 ml injections (~ 6.7 units) into 30 detrusor muscle sites.
Reconstituted BOTOX (200 units / 30ml) is injected into the detrusor muscle via a rigid or flexible cystoscope, avoiding the trine. Instill sufficient saline into the bladder in order to obtain "adequate visualization for the injections, but avoiding" excessive distension.
To remove any air that is present, the injection needle must be filled with approximately 1 ml of solution (depending on the length of the needle) before starting the injections.
Insert the needle into the detrusor muscle for about 2 mm and perform 30 injections of 1 ml each (total volume 30 ml) about 1 cm apart (see diagram). For the final injection, inject about 1 ml of physiological solution normal sterile in order to administer the full dose. Once the injections have been performed, drain the physiological solution used to visualize the bladder wall. Observe the patient for at least 30 minutes after the injections.
Clinical improvement is generally seen within 2 weeks. Evaluate the possibility of reintroducing patients to a new course of treatment if the clinical effect of previous treatment decreases (the median duration in Phase III clinical trials was 256-295 days for 200 units of BOTOX), but not before 3 months have passed since the previous injections into the bladder.
Chronic migraine
Diagnosis of chronic migraine and administration of BOTOX should only be performed under the supervision of neurologists experienced in the treatment of chronic migraine.
The recommended dose of reconstituted BOTOX for the treatment of chronic migraine is between 155 and 195 units administered intramuscularly (IM) via a 0.5 inch 30 gauge needle with injections divided between 7 specific areas of the head muscles and of the neck.
It may be necessary to use a 1 inch needle in the cervical region for patients with extremely thick cervical muscles. With the exception of the procerus muscle, where only one site (midline) should be injected, all other muscles need to be injected bilaterally, with half the injections given on the left and half on the right side of the head and head. In the case of predominant painful site or sites, it is possible to administer further injections on one or both sides in a maximum of 3 specific muscle groups (occipital, temporal and trapezius), up to the maximum dose per muscle.
The recommended reprocessing schedule is every 12 weeks.
BOTOX dosage per muscle for chronic migraine:
For all indications
In the event of treatment failure after the first course of therapy, for example of the absence, one month after the injection, of a significant clinical improvement compared to baseline, it is necessary to carry out the following actions:
• clinical verification, which may include an electromyographic examination in a specialist context, of the action of the toxin on the injected muscle (s);
• analysis of the causes of the failure, eg. a bad choice of muscles to inject, an insufficient dose, an incorrect injection technique, the appearance of a fixed contracture, too weak antagonist muscles, the formation of toxin neutralizing antibodies;
• re-evaluation of the appropriateness of treatment with botulinum toxin type A;
• in the absence of side effects secondary to the first course of treatment, institute a second course of treatment as follows: i) adjust the dose, taking into account the analysis of previous therapy failure; ii) use EMG technique; and iii) observe an interval of three months between the two subsequent courses of therapy.
In the event of therapy failure or diminished effect after repeated injections, alternative therapy methods should be employed.
04.3 Contraindications
BOTOX is contraindicated:
• in subjects with known hypersensitivity to botulinum toxin type A, or to any of the excipients;
• in the presence of infection at the proposed injection sites.
BOTOX for the treatment of urinary incontinence due to neurogenic overactivity of the bladder detrusor is also contraindicated:
• in patients who present with urinary tract infections at the time of treatment;
• in patients with acute urinary retention at the time of treatment, who do not routinely undergo catheterization;
• in patients unwilling and / or unable to initiate post-treatment catheterization, if necessary.
04.4 Special warnings and appropriate precautions for use
Before administering BOTOX it is necessary to be aware of the relative normal anatomy of the affected area and of any abnormal anatomical situation due to previous surgery and inoculation of previously injured anatomical structures should be avoided. Serious adverse reactions including fatal outcomes have been reported in patients who had received unspecified injections of BOTOX directly into the salivary glands, orlo-lingual-pharyngeal region, esophagus and stomach Some patients had pre-existing dysphagia or significant debilitation.
The recommended doses and frequencies for BOTOX administration should not be exceeded.
Severe and / or immediate hypersensitivity reactions including anaphylaxis, serum disease, urticaria, mild tissue edema and dyspnoea have been reported rarely. Some of these reactions have been reported following the use of BOTOX alone or with other products that are found to cause similar reactions.
If such reactions occur, avoid treating the patient with a new injection of BOTOX and immediately initiate appropriate medical therapy, for example with epinephrine. A case of anaphylaxis has been reported involving a patient who died after injection of inappropriately diluted BOTOX. with 5 ml of 1% lidocaine (see "Further information" in section 4.8).
Adverse reactions have been reported due to spread of the toxin distant from the point of administration (see section 4.8), sometimes resulting in death, sometimes associated with dysphagia, pneumonia and / or profuse asthenia.
Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with underlying neurological disorders, including swallowing difficulties, are at increased risk for these reactions. The botulinum toxin product should be used in these patients under specialist supervision and should only be used if the benefit of the treatment is considered to outweigh the risk. Patients with a history of dysphagia and aspiration pneumonia should be treated with extreme caution.
Patients or caregivers should be advised to seek immediate help in the event of swallowing, speech or breathing disorders.
Dysphagia has also been reported after inoculation at sites other than cervical muscles (see section 4.4 "cervical dystonia").
Clinical fluctuations during repeated use of BOTOX (as with all botulinum toxins) may be due to different vial reconstitution procedures, injection intervals, injected muscles and small different potency values given by the biological test used.
The formation of antibodies neutralizing botulinum toxin type A can reduce the effectiveness of treatment with BOTOX due to the inactivation of the biological activity of the toxin. The results of some studies suggest that the use of BOTOX at more frequent intervals or at higher doses may result in a higher incidence of antibody formation. When appropriate, the potential risk of antibody formation can be minimized by injecting the most effective dose. low administered with a longer, clinically appropriate interval between treatments.
As with any treatment that may allow patients who previously led a sedentary lifestyle to resume their activities, the sedentary patient should be advised to resume their activity gradually.
Caution should be exercised when using BOTOX in the presence of "inflammation at the chosen injection site (s)" or when excessive weakness or atrophy is observed in the target muscle. Caution should be exercised. also when using BOTOX to treat patients with peripheral motor neuropathic diseases (such as lateral amyotrophic sclerosis or motor neuropathy).
BOTOX should be used with particular caution and under careful supervision in patients with clinical or subclinical evidence of neuromuscular transmission defect, eg, myasthenia gravis or Lambert-Eaton syndrome; such patients may have increased sensitivity to agents, such as BOTOX, which can lead to excessive muscle weakness. Patients with neuromuscular disorders may be at increased risk for clinically significant systemic reactions including severe dysphagia and respiratory impairment with typical BOTOX dosage.
As with any injection, procedure-related damage can occur. An injection can lead to localized infection, pain, inflammation, paraesthesia, hypoesthesia, soreness, swelling, erythema, and / or bleeding / bruising. Pain related to needle use and / or anxiety can lead to a vasovagal response, such as syncope, hypotension, etc. Care should be taken when injecting near weak anatomical areas.
Pneumothorax associated with the injection procedure has been reported following administration of BOTOX close to the chest. Care should be taken when injecting near the lungs, particularly in the apical area.
Pediatric use
The safety and efficacy of BOTOX in indications other than those described in section 4.1 for the pediatric population have not been established. Post marketing reports of possible distant spread of the toxin in pediatric patients with comorbidities, mainly with paralysis, have been reported very rarely. In general, the dose used in these cases was in excess of the recommended dose (see section 4.8).
There have been rare reports of spontaneous deaths sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including cases of off-indications (e.g. neck area) use. Extreme caution should be exercised when treating patients who have significant neurological weakness, dysphagia, or have recently had aspiration pneumonia or lung disease. Treatment in patients with poor underlying health status should only be undertaken if the potential benefit to the patient is considered to outweigh the risks.
Blepharospasm
The reduction in blinking caused by the injection of botulinum toxin into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with 7th nerve disorder. It is advisable to carry out a careful examination of the corneal sensitivity in previously operated eyes, to avoid the injection in the lower eyelid area to avoid ectropion, and to adopt an effective preventive treatment of any epithelial defect. This may require the use of eye drops, ophthalmic ointments, soft therapeutic contact lenses, or closing the eye by bandaging or other means.
Bruising can easily occur in the soft tissues of the eyelid. This can be minimized by gently squeezing the injection site immediately after the injection.
Due to the anticholinergic activity of botulinum toxin, particular caution should be exercised in the treatment of patients at risk of narrow-angle glaucoma, including patients with anatomically narrow angles.
Cervical dystonia
Patients with cervical dystonia should be advised of the possibility of dysphagia which can be very mild but also severe. Dysphagia can persist for up to 2-3 weeks after injection but has been described to last for up to 5 months after injection.
As a consequence of dysphagia there is the possibility of aspiration, dyspnoea and sometimes the need for tube feeding. In rare cases, dysphagia followed by aspiration pneumonia and death has been reported.
Limiting the dose injected into the sternocleidomastoid muscle to a dose below 100 Units may reduce the occurrence of dysphagia. Patients with smaller neck muscle mass or patients receiving injections in both sides of the sternocleidomastoid muscle have been described as being at increased risk for dysphagia. Dysphagia is attributable to the spread of the toxin into the musculature of the esophagus. Injections into the levator scapulae muscle may be associated with an increased risk of upper respiratory tract infection and dysphagia.
Dysphagia may help decrease food and water intake resulting in weight loss and dehydration. Patients with subclinical dysphagia may be at increased risk of severe dysphagia after BOTOX injection.
Focal spasticity associated with infantile cerebral palsy and spasticity of the hand and wrist in adult post-stroke patients
BOTOX is a treatment for focal spasticity only studied in association with other standard care regimens, and is not intended as a substitute for such therapy modalities. BOTOX is not likely to be effective in improving range of motion in a joint with persistent pathological contracture.
Post marketing reports of possible spread of the toxin in pediatric patients with comorbidities, predominantly with cerebral palsy, have been reported rarely. In general the dose used in these cases was higher than the recommended one (see section 4.8).
Rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy have been reported following treatment with botulinum toxin. Particular care should be taken when treating pediatric patients with significant neurological debility, dysphagia, or a recent history of aspiration pneumonia or lung disease.
Primary hyperhidrosis of the armpits
Medical history and physical examination of the patient, as well as any further investigations that may be deemed necessary, should be performed in order to rule out potential causes of secondary hyperhidrosis (eg hyperthyroidism, pheochromocytoma). This will avoid symptomatic treatments of hyperhidrosis without diagnosis and / or treatment of underlying diseases.
Urinary incontinence due to neurogenic detrusor overactivity
Physicians should exercise caution when performing cystoscopy.
In patients not undergoing catheterization, the post-void residual urinary volume should be assessed within 2 weeks of treatment and periodically according to the physician's opinion for up to 12 weeks. Advise patients to consult their physician if they experience difficulty urinating as catheterization may be required.
Autonomic dysreflexia associated with the procedure may occur. An immediate check-up of the treated patient may be necessary.
Chronic migraine
Safety and efficacy have not been established in the prophylaxis of headaches in patients with episodic migraine (headaches for chronic tension-type headache. The safety and efficacy of BOTOX in patients with drug overuse headache (secondary headache disorder) have not been studied.
04.5 Interactions with other medicinal products and other forms of interaction
Theoretically, the effect of botulinum toxin can be enhanced by aminoglycoside antibiotics or spectinomycin, or by other drugs that interfere with neuromuscular transmission (eg neuromuscular blocking agents).
The effect of concurrent administration or within several months of different serotypes of botulinum neurotoxin is not known. Administration of another botulinum toxin before the effects of a previously administered botulinum toxin have completed may cause worsening of neuromuscular weakness. .
No interaction studies have been performed. No interactions of clinical importance were reported.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data on the use of botulinum toxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown. BOTOX should not be used during pregnancy and in women of childbearing age who do not use contraceptives unless clearly necessary.
Feeding time
There is no information on the excretion of BOTOX in milk. The use of BOTOX during breastfeeding is not recommended.
Fertility
There are no adequate data on the effects on fertility resulting from the use of botulinum toxin type A in fertile women. Studies in rats of both sexes have shown decreased fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. However, BOTOX can cause asthenia, muscle weakness, dizziness and visual disturbances which could affect driving and use of machines.
04.8 Undesirable effects
General
In controlled clinical trials, adverse events believed by investigators to be related to BOTOX were reported in 35% of patients with blepharospasm, in 28% of patients with cervical dystonia, in 17% of patients with infantile cerebral palsy, in 11 % of patients with primary axillary hyperhidrosis and in 16% of patients with focal upper limb spasticity associated with stroke. In clinical trials for urinary incontinence due to neurogenic overactivity of the bladder detrusor, the incidence was 32% with the first treatment and was reduced to 18% with a second treatment. In clinical trials for chronic migraine, the incidence was 26% with the first treatment and decreased to 11% with the second treatment.
In general, adverse reactions occur within the first few days after injection and, usually transient, may last for several months or, in rare cases, longer.
Localized muscle weakness represents the expected pharmacological effect of botulinum toxin in muscle tissue.
As expected for any injection procedure, localized pain, inflammation, paraesthesia, hypoesthesia, soreness, swelling / edema, erythema, localized infection, bleeding and / or bruising have been associated with the injection. Needle pain and / or anxiety it can result in a vasovagal response, including transient symptomatic hypotension and syncope Fever and flu syndrome have also been reported after botulinum toxin inoculation.
Adverse reactions - frequency by indication
The frequency of adverse reactions by indication, documented during clinical trials, is given below.
Frequency is defined as follows: very common (> 1/10); common (> 1/100 to 1 / 1,000 to 1 / 10,000 to
Blepharospasm / Hemifacial spasm
Nervous system disorders
Uncommon: dizziness, facial paresis and facial paralysis.
Eye disorders
Very common: eyelid ptosis.
Common: punctate keratitis, lagophthalmos, dry eye, photophobia, eye irritation and increased lacrimation.
Uncommon: keratitis, ectropion, diplopia, entropion, visual disturbances and blurred vision.
Rare: edema of the eyelid.
Very rare: ulcerative keratitis, alteration of the corneal epithelium, corneal perforation.
Skin and subcutaneous tissue disorders
Common: bruising.
Uncommon: rash / dermatitis.
General disorders and administration site conditions
Common: facial irritation and edema.
Uncommon: exhaustion.
Cervical dystonia
Infections and infestations
Common: rhinitis and upper respiratory tract infection.
Nervous system disorders
Common: dizziness, hypertonia, hypoesthesia, somnolence and headache.
Eye disorders
Uncommon: diplopia and eyelid ptosis.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea and dysphonia.
Gastrointestinal disorders
Very common: dysphagia (see section "Further information").
Common: dry mouth and nausea.
Musculoskeletal and connective tissue disorders
Very common: muscle weakness.
Common: musculoskeletal stiffness and soreness.
General disorders and administration site conditions
Very common: pain.
Common: asthenia, flu-like symptoms and malaise.
Uncommon: fever.
Infantile cerebral palsy
Infections and infestations
Very common: viral infection and ear infection.
Nervous system disorders
Common: somnolence, uncoordinated walking and paraesthesia.
Skin and subcutaneous tissue disorders
Common: skin rash.
Musculoskeletal and connective tissue disorders
Common: myalgia, muscle weakness and pain in extremities.
Renal and urinary disorders
Common: urinary incontinence.
Injury, poisoning and procedural complications
Common: falls.
General disorders and administration site conditions
Common: malaise, injection site pain and asthenia.
Focal spasticity of the upper limb associated with stroke
Psychiatric disorders
Uncommon: depression and insomnia.
Nervous system disorders
Common: hypertonia.
Uncommon: hypoesthesia, headache, paraesthesia, lack of coordination and amnesia.
Ear and labyrinth disorders
Uncommon: vertigo.
Vascular pathologies
Uncommon: orthostatic hypotension.
Gastrointestinal disorders
Uncommon: oral nausea and paraesthesia.
Skin and subcutaneous tissue disorders
Common: ecchymosis and purpura.
Uncommon: dermatitis, pruritus and rash.
Musculoskeletal and connective tissue disorders
Common: pain in extremity and muscle weakness.
Uncommon: arthralgia and bursitis.
General disorders and administration site conditions
Common: injection site pain, fever, flu syndrome, haemorrhage and injection site irritation.
Uncommon: asthenia, pain, injection site hypersensitivity, malaise and peripheral edema.
Some of the uncommon events may be related to the disease.
Primary hyperhidrosis of the armpits
Nervous system disorders
Common: headache and paraesthesia.
Vascular pathologies
Common: hot flashes.
Gastrointestinal disorders
Uncommon: nausea.
Skin and subcutaneous tissue disorders
Common: hyperhidrosis (non-axillary sweating), abnormal skin odor, pruritus, subcutaneous lump and alopecia.
Musculoskeletal and connective tissue disorders
Common: pain in the extremities.
Uncommon: muscle weakness, myalgia and arthropathy.
General disorders and administration site conditions
Very Common: injection site pain.
Common: pain, injection site edema, injection site haemorrhage, injection site hypersensitivity, injection site irritation, asthenia and injection site reactions.
In the treatment of primary axillary hyperhidrosis, increased non-axillary sweat was reported in 4.5% of patients, within 1 month of inoculation, without direct reference to the anatomical sites involved.
This effect resolved in approximately 30% of patients within 4 months.
Upper limb weakness was also reported as uncommon (0.7%), mild, transient, requiring no treatment and resolving without sequelae. This adverse reaction may be related to the treatment, the injection technique, or both. In the uncommon case of muscle weakness reported after treatment, a neurological examination may be required.
Furthermore, it may be necessary to re-evaluate the inoculation technique in subsequent treatments in order to ensure an intradermal positioning of the inoculum.
In an uncontrolled safety study with BOTOX (50 U per armpit) in pediatric patients 12 to 17 years of age (N = 144), adverse reactions that occurred in more than one single patient (every 2 patients) included injection site pain and hyperhidrosis (non-axillary sweating).
Urinary incontinence due to neurogenic overactivity of the bladder detrusor
Infections and infestations
Very common: urinary tract infections.
Psychiatric disorders
Common: insomnia.
Gastrointestinal disorders
Common: constipation.
Musculoskeletal and connective tissue disorders
Common: muscle weakness, muscle spasm.
Renal and urinary disorders
Very common: urinary retention.
Common: haematuria *, dysuria *, bladder diverticulum.
General disorders and administration site conditions
Common: fatigue, walking disturbances.
Injury, poisoning and procedural complications
Common: autonomic dysreflexia *, falls.
* procedure related adverse reactions
In clinical studies, urinary tract infections were reported in 49.2% of patients treated with 200 U of BOTOX and in 35.7% of patients treated with placebo (53.0% of patients with multiple sclerosis treated with 200 U compared to 29.3% treated with placebo; 45.4% of patients with spinal cord injury treated with 200 U compared to 41.7% treated with placebo). Urinary retention was reported in 17.2% of patients treated with 200 U of BOTOX and in 2.9% of patients treated with placebo (28.8% of patients with multiple sclerosis treated with 200 U compared to 4.5% treated with with placebo; 5.4% of patients with spinal cord injury treated with 200 U versus 1.4% treated with placebo).
No change in the type of adverse reactions was observed with repeat dosing.
There was no difference in the annualized rate of multiple sclerosis (MS) flare-ups (i.e. the number of MS flare-ups per patient-year) (BOTOX = 0.23, placebo = 0.20) in MS patients in the pivotal studies.
Among patients not catheterized at baseline before treatment, catheterization was initiated in 38.9% after treatment with 200 units of BOTOX compared with 17.3% with placebo.
Chronic migraine
Nervous system disorders
Common: headache, migraine, facial paresis.
Eye disorders
Common: eyelid ptosis.
Skin and subcutaneous tissue disorders
Common: pruritus, rash.
Uncommon: skin pain.
Musculoskeletal and connective tissue disorders
Common: neck pain, myalgia, musculoskeletal pain, arthralgia, musculoskeletal pain, muscle spasms, muscle stiffness and muscle weakness.
Uncommon: pain in the jaw.
General disorders and administration site conditions
Common: pain at the injection site.
Gastrointestinal disorders
Uncommon: dysphagia.
The discontinuation rate due to adverse events in these Phase III studies was 3.8% for BOTOX and 1.2% for placebo.
Further information
Dysphagia ranges from mild to severe, with aspiration potential occasionally requiring medical attention (see section 4.4).
Adverse reactions (exaggerated muscle weakness, dysphagia, constipation, aspiration / aspiration pneumonia, with fatal outcome in some cases) related to diffusion of toxin distant from the administration site have been reported rarely (see section 4.4).
Since the medicine has been on the market, the following other adverse reactions have been reported: muscle denervation / atrophy; respiratory depression and / or respiratory failure; aspiration pneumonia; dysarthria; strabismus, peripheral neuropathy; abdominal pain; blurred vision; visual disturbances; fever; facial paralysis; facial paresis; hypoesthesia; malaise; myalgia; itch; hyperhidrosis; alopecia (including madarosis); diarrhea; anorexia; hearing loss; tinnitus; dizziness; radiculopathy; syncope; myasthenia gravis; paraesthesia; erythema multiforme; psoriasiform dermatitis; vomiting and brachial plexopathy.
There have also been rare reports of adverse effects affecting the cardiovascular system, including arrhythmias and myocardial infarction, some of which were fatal. Some of these patients had risk factors, including cardiovascular disease.
Severe and / or immediate hypersensitivity reactions, such as anaphylaxis and serum disease, as well as other manifestations of hypersensitivity including urticaria, soft tissue edema and dyspnoea have been reported rarely. Some of these reactions have been reported following the use of BOTOX alone or with other agents known to cause similar reactions.
Closed-angle glaucoma has been reported very rarely after botulinum toxin treatment for blepharospasm.
There have been reports of initial or recurrent seizures, especially in patients predisposed to these types of reactions. The exact relationship of these events with botulinum toxin injections has not been established.
In children, these reactions have been reported predominantly in individuals with cerebral palsy treated for spasticity.
Pain associated with the use of the needle and / or anxiety can cause a vasovagal response.
04.9 Overdose
The concept of BOTOX overdose is relative and depends on the dose, the injection site, and the background characteristics of the tissue. No cases of systemic toxicity have been observed following accidental inoculation of BOTOX. Excessive dosages can result in local, or distant, generalized and profound neuromuscular paralysis.
No cases of ingestion of BOTOX have been observed.
The signs and symptoms of overdose are not evident immediately after injection. In the event of accidental injection or ingestion or suspected overdose, the patient should be monitored clinically for several weeks for any signs and symptoms of muscle weakness which may be local or distant from the injection site which may include ptosis, diplopia, dysphagia, dysarthria, generalized asthenia, or respiratory failure. These patients should undergo further medical evaluation and appropriate medical treatment established immediately, which may also require hospitalization.
If the muscles of the oropharynx and esophagus are affected, aspiration can occur which can lead to the development of aspiration pneumonia. In the case of paralysis of the respiratory muscles or sufficient weakening, it will be necessary to resort to intubation and assisted breathing, until recovery and also involve the need for a trecheostomy and prolonged mechanical ventilation in addition to other general supportive care.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other peripherally acting muscle relaxants.
ATC code M03A X01
Botulinum toxin type A blocks the peripheral release of acetylcholine at the presynaptic cholinergic nerve endings by disrupting the release of SNAP-25, a protein that complements the successful collection and release of acetylcholine from vesicles located in nerve endings.
After injection, an initial rapid high-affinity binding of the toxin to specific cell surface receptors occurs. This is followed by transfer of the toxin across the plasma membrane by receptor-mediated endocytosis. Finally, the toxin is released into the cytosol.
This latter process is accompanied by a progressive inhibition of acetylcholine release, and clinical signs occur within 2-3 days with a maximum effect observed within 5-6 weeks after injection.
Recovery, after intramuscular inoculation, normally occurs within 12 weeks after injection as the nerve endings regenerate and reconnect with the terminal plates. After intradermal inoculation, where the target is the exocrine sweat glands, the effect lasted a mean of 7.5 months after the first injection in patients treated with 50 Units per axilla However, in 27.5% of patients the duration of the effect was 1 year or more. Restoration of sympathetic nerve endings of the sweat glands after intradermal inoculation with BOTOX has not been studied.
BOTOX, following intradetrusorial injection, has effects on the efferent pathways of the detrusor activity itself by inhibiting the release of acetylcholine. Furthermore BOTOX can inhibit the release of afferent neurotransmitters and the pathways of sensitivity.
CLINICAL STUDIES
Primary hyperhidrosis of the armpits
A double-blind, multicenter clinical study was conducted in patients who had persistent bilateral primary axillary hyperhidrosis, established at baseline, by gravimetric measurement, equal to at least 50 mg of spontaneous sweat produced by each armpit for more than 5 minutes at room temperature, to rest. Three hundred and twenty patients were randomized to receive 50 Units of BOTOX (N = 242) or placebo (N = 78). Responder patients were defined as having a reduction from baseline of at least 50% in axillary sweating.
At the primary endpoint, 4 weeks post-injection, the response rate in the BOTOX-treated group was 93.8%, compared to 35.9% in the placebo-treated patients (p
The incidence of responding patients among those treated with BOTOX continued to be significantly higher (p
In an open-label follow-up clinical study, 207 eligible patients were enrolled who received up to 3 treatments of BOTOX. Specifically, 174 patients completed the full 16-month duration of the 2 pooled studies (4-month double-blind study and 12-month follow-up to open-label study). The incidence of clinical response at week 16 after the first ( n = 287), second (n = 123) and third (n = 30) treatment were 85.0%, 86.2% and 80% respectively. The mean duration of effect based on the combined single-dose continuation study and the open-label study was 7.5 months from the first treatment; in addition, in 27.5% of patients the duration of the effect lasted for 1 year or more.
There is limited clinical trial experience on the use of BOTOX in axillary hyperhidrosis in children between 12 and 18 years of age.
A single, one-year, uncontrolled, repeat-dose safety study was conducted in the United States in pediatric patients aged 12-17 years (N = 144) with severe primary hyperhidrosis of the axillae. Patients were mainly female (86.1%) and Caucasians (82.6%). Patients were treated at a dose of 50 U per armpit for a total of 100 U per patient per treatment. However, no dosing studies have been conducted in adolescents and therefore no recommendation on a posology can be made. The efficacy and safety of BOTOX in this patient group have not been definitively established.
Urinary incontinence due to neurogenic detrusor overactivity
Two multicentre, randomized, double-blind, placebo-controlled Phase III clinical trials were conducted in patients with urinary incontinence due to neurogenic detrusor overactivity, capable of spontaneous urination or using a catheter. A total of 691 patients with spinal cord injury or multiple sclerosis, inadequately managed with at least one anticholinergic agent, were enrolled. These patients were randomized to receive 200 units of BOTOX (n = 227), 300 units of BOTOX (n = 223) or placebo (n = 241).
In both Phase III studies, significant improvements in favor of BOTOX (200 units and 300 units) over placebo were observed in the primary efficacy variable of change from baseline in weekly incontinence frequency at the time of primary efficacy detection. at week 6, including the percentage of patients without incontinence episodes. Significant improvements were observed in urodynamic parameters, including increases in maximum cystometric capacity and decreases in peak detrusor pressure during the first involuntary detrusor contraction. Improvements were also observed. Significant, compared to placebo, in patient-reported scores of health-related and incontinence-specific quality of life as measured by the Incontinence Quality of Life (I-QOL) questionnaire (including limiting avoidance behavior, "psychosocial impact and" social embarrassment). No additional benefit was shown with 300 units of BOTOX compared to 200 units and a more favorable safety profile was observed with 200 units of BOTOX.
The results of the pivotal studies with summary data are shown below:
Primary and secondary endpoints at baseline and change from baseline in pooled pivotal studies:
The median duration of response in the two pivotal studies, based on re-treatment request, was 256-295 days (36-42 weeks) for the 200 dose units group, compared with 92 days (13 weeks) with placebo.
For all efficacy endpoints, patients had responses consistent with re-treatment.
In the pivotal studies, none of the 475 patients with neurogenic detrusor overactivity in the samples tested developed neutralizing antibodies.
Chronic migraine
BOTOX blocks the release of neurotransmitters associated with the pathogenesis of pain. The mechanism of action of BOTOX in symptomatic relief in chronic migraine has not been fully understood.
Clinical and preclinical pharmacodynamic studies suggest that BOTOX suppresses peripheral sensitization, therefore probably also inhibiting central sensitization.
The table below shows the main results obtained from the pooled efficacy analysis after two treatments with BOTOX given at 12-week intervals in two Phase III clinical trials in patients with chronic migraine, who experienced at least 4 episodes and suffered from headache for ≥ 15 days (with at least 4 hours of continuous headache), with at least 50% headache days for both migraine and probable migraine.
Although the studies did not have sufficient significance to demonstrate subgroup differences, the treatment effect appeared less in the male (N = 188) and non-Caucasian (N = 137) patients group than in the entire study population.
05.2 Pharmacokinetic properties
General characteristics of the active ingredient
Distribution studies performed in rats indicated slow muscle diffusion of the 125I-botulinum neurotoxin complex type A into the gastrocnemius muscle after injection, followed by rapid systemic metabolism and elimination in urine. The amount of radiolabelled material in the muscle decreased with a half-life of about 10 hours. At the injection site the radioactivity was bound to large protein molecules, while in the plasma it was bound to small molecules, suggesting a rapid systemic substrate metabolism. Within 24 hours of administration, 60% of the radioactivity was excreted in the urine. Probably the toxin is metabolized by proteases and the molecular components are recycled through the normal metabolic pathways.
Due to the nature of the product, the classical studies on the absorption, distribution, biotransformation and elimination of the active principle have not been performed.
Characteristics in patients
Therapeutic doses of BOTOX are thought to cause poor systemic distribution. Clinical studies performed with single-fiber electromyography techniques have demonstrated increased neuromuscular electrophysiological activity in muscles distant from the injection site, not accompanied by any clinical signs or symptoms.
05.3 Preclinical safety data
Reproduction Studies
By subjecting pregnant mice, rats, and rabbits to intramuscular injections of BOTOX during the period of organogenesis, the No Observable Adverse Effect Level (NOAEL) on development was 4, 1 and 0.125 Units / kg, respectively. Higher doses were associated. with decreased fetal body weight and / or delayed ossification and abortions were observed in rabbits.
Fertility and reproduction
By subjecting male and female rats to intramuscular injections of BOTOX, the reproductive NOEL was 4 and 8 Units / kg, respectively. Higher doses were associated with dose-dependent reductions in fertility.
Once fertilization had occurred, there were no adverse effects on the number or viability of embryos desired or conceived from treated male and female rats.
Other studies
In addition to the reproductive toxicology studies, the following pre-clinical safety studies were performed for BOTOX: acute toxicity, repeated dose toxicity, local tolerance, mutagenicity, antigenicity, compatibility with human blood. These studies did not reveal any special risks for humans at clinically relevant dose levels. The maximum recommended dose for a treatment session is 300 Units (corresponding to 6 Units / Kg in a 50 kg person). The published intramuscular LD50 in juvenile monkeys is 39 Units / Kg.
No systemic toxicity was observed following a single intradetrusorial injection of prostatic urethra and proximal rectum, seminal vesicle and urinary bladder wall or monkey uterus (~ 3 units / kg) with no adverse effects. 9 months with repeated doses injected into the detrusor muscle (4 injections), ptosis was observed with 24 units / kg and mortality at doses ≥24 units / kg. Muscle fiber degeneration / regeneration was observed in the skeletal muscles of animals at which it was a dose of at least 24 units / kg was administered. These myopathic changes were considered secondary effects of systemic exposure. Furthermore, the degeneration of muscle fibers was observed in one animal subjected to a dosage of 12 units / kg. The lesion in this animal was of minimal severity and was considered not associated with any clinical manifestations. It was not possible to determine with certainty whether it was related to BOTOX treatment. The dose of 12 units / kg corresponds to a 3-fold greater exposure to BOTOX than the recommended clinical dose of 200 units for urinary incontinence due to neurogenic overactivity of the detrusor muscle (in a 50 kg person).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Human albumin
Sodium chloride
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other products.
06.3 Period of validity
3 years.
Microbiological and potency studies have shown that the product can be stored for up to 5 days at 2 ° -8 ° C after reconstitution.
In-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2 ° C - 8 ° C.
After reconstitution in the vial, stability of the product has been demonstrated for 24 hours at 2 ° C - 8 ° C.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C), or in a freezer (-5 ° C or below).
For storage conditions of the reconstituted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Type I colorless glass vial, nominal capacity of 10 ml, equipped with a chlorobutyl rubber stopper and a tamper evident aluminum seal.
The packs can be of 1, 2, 3, 6 or 10 vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
It is good practice to reconstitute the vial and prepare the syringe on top of the plasticized absorbent paper, in order to collect any spilled product.
BOTOX should only be reconstituted with sterile sodium chloride 9 mg / ml (0.9%) solution for injection. The appropriate amount of diluent should be drawn with a syringe (see section 4.2 for dilution instructions for urinary incontinence due to neurogenic overactivity of the detrusor muscle).
Dilution table for the BOTOX 100 Allergan Unit pack for all other indications:
If packs with different strengths of BOTOX are used during the same treatment, take special care to use the right amount of diluent to reconstitute the specific number of units per 0.1ml. The amount of diluent varies between BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe must be properly labeled.
Since BOTOX is denatured by effervescence or vigorous agitation, the diluent should be slowly injected into the vial. The vial should be discarded if the strength of its vacuum is not such as to draw the diluent into the vial. Reconstituted BOTOX should be a clear colorless or pale yellow solution, without particles. The reconstituted solution must be visually checked before use for clarity and absence of particles. Once reconstituted in the vial, BOTOX can be stored in the refrigerator (2-8 ° C) for up to 24 hours before use. The date and time of reconstitution should be indicated in the space provided on the label.
When further diluting BOTOX for urinary incontinence in a syringe, it must be used immediately. This product is for single use only and any remaining unused solution should be discarded.
For safety, unused vials should be reconstituted with a small amount of water and then autoclaved. Any unused vials, syringes, and spilled material should be autoclaved, or any residual BOTOX should be rendered inactive by using a sodium hypochlorite solution (0.5%) for 5 minutes.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport
County Mayo
Ireland
Sales representative in Italy
Allergan SpA, Via Salvatore Quasimodo n ° 134/138, Rome
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 034883013 / M "100 Units Allergan powder for solution for injection" 1 vial contains 100 Allergan Units
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 4 August 2000
Renewal: February 28, 2009
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 23 January 2013
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