GRADIENT POLIFARMA - PACKAGE LEAFLET - LEAFLETS

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Gradient Polifarma - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Flunarizine (Flunarizine dihydrochloride)

Gradient Polifarma 5 mg hard capsules

Indications Why is Gradient Polifarma used? What is it for?

Gradient Polifarma contains flunarizine dihydrochloride, which belongs to a group of medicines that relax blood vessels so that blood can flow more easily to the brain.

Gradient Polifarma is indicated in adults to prevent migraine (headache) which occurs with frequent and severe attacks. Gradient Polifarma is used when other therapies have not worked or have caused serious side effects.

Talk to your doctor if you don't feel better or if you feel worse.

Contraindications When Gradient Polifarma should not be used

Do not take Gradient Polifarma

if you are allergic to flunarizine dihydrochloride or any of the other ingredients of this medicine (listed in section 6)
if you have or have suffered from depression
if you suffer from symptoms of Parkinson's disease (a disease that prevents movement control, manifested for example by tremor, muscle stiffness, slowing of movement)
if you suffer from extrapyramidal disorders (movement control disorders).

Precautions for use What you need to know before taking Gradient Polifarma

Talk to your doctor or pharmacist before taking Gradient Polifarma.

During treatment and especially during maintenance therapy:

you may experience serious side effects such as excessive tiredness, movement disturbances or depression. At the first signs of these disorders, tell your doctor immediately (see section "Possible side effects");
your doctor will monitor you regularly for serious side effects in order to stop treatment promptly, especially if you are elderly (see section "Possible side effects");
if your doctor does not notice any improvement or a loss of the effect of this medicine, he will consider stopping the treatment (see section "How to take Gradient Polifarma").

Interactions Which drugs or foods can modify the effect of Gradient Polifarma

Other medicines and Gradient Polifarma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Tell your doctor if you are taking the following medicines, as co-administration with Gradient Polifarma can cause excessive sedation (physical and mental relaxation):

hypnotics (sleeping pills, substances that help sleep)
tranquilizers (medicines to treat anxiety) Tell your doctor if you are taking the following medicines, as co-administration may affect Gradient Polifarma:
topiramate, phenytoin, carbamazepine, valproate and phenobarbital (used to treat epilepsy)

Gradient Polifarma with alcohol

Avoid drinking alcoholic beverages during Gradient Polifarma therapy, as the simultaneous administration of Gradient Polifarma with alcohol can cause excessive sedation (physical and mental relaxation).

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Do not take this medicine during pregnancy and breastfeeding, as the safety of use has not been established during pregnancy and breastfeeding.

Driving and using machines

Pay particular attention if you have to drive or use machinery or carry out operations that require perfect clarity, as Gradient Polifarma, especially in the initial phase of therapy, can cause drowsiness.

Gradient Polifarma contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Gradient Polifarma: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Adults

Initial attack therapy

If you are under the age of 65, the recommended starting dose is 10 mg per day (1 capsule of 10 mg or 2 capsules of 5 mg, as prescribed by your doctor), to be taken in the evening at bedtime. Do not exceed the doses prescribed by your doctor.

Maintenance therapy

If your doctor thinks that you have responded positively to the initial attack therapy, he will prescribe maintenance therapy. During maintenance therapy, your doctor will reduce your dose and make you take this medicine every other day for 5 consecutive days, with interruption. two days each week, for example Monday, Wednesday and Friday with a break on Saturday and Sunday Do not exceed the doses prescribed by your doctor.

Senior citizens

If you are over 65 the recommended starting dose is 5 mg per day (1 capsule of 5 mg). Do not exceed the doses prescribed by your doctor.

Duration of treatment

The duration of the initial attack therapy is 2 months.
If after 2 months from the start of treatment, your doctor believes that you have responded positively to the initial attack therapy, he will prescribe maintenance therapy for 6 months.
After 6 months of maintenance therapy, your doctor will make you stop taking Gradient Polifarma, even if you have responded positively to the treatment.
If during the 6 months of maintenance therapy the doctor notices a loss of the effect of this medicine or the presence of side effects, the doctor will consider whether to stop the treatment with Gradient Polifarma.
Your doctor will be able to restart Gradient Polifarma therapy only in case of relapse.

Overdose What to do if you have taken an overdose of Gradient Polifarma

If you take more Gradient Polifarma than you should

If you take too much of this medicine, tell your doctor immediately or go to the nearest hospital where you will be given the most appropriate treatment. If you take too much of this medicine you may have the following symptoms:

sedation (physical and mental relaxation)
asthenia (weakness)
agitation
tachycardia (increased heart rate per minute).

Treatment

The doctor will use appropriate supportive therapy with induction of vomiting, activated charcoal, gastric lavage, as well as other supportive therapies to reduce symptoms. A specific antidote is not known

If you forget to take Gradient Polifarma

Do not take a double dose to make up for a forgotten capsule.

If you stop using Gradient Polifarma

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

Side Effects What are the side effects of Gradient Polifarma

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If during the treatment with Gradient Polifarma you experience the following serious side effects, inform your doctor immediately that you STOP the treatment with Gradient Polifarma:

progressive increase in asthenia (excessive weakness)
depression, for which women who have suffered from depression in the past were most at risk (see "Do not take Gradient Polifarma")
extrapyramidal symptoms (movement control disorders; see "Do not take Gradient Polifarma") such as: - difficulty in starting a new movement of your body, with consequent slowing down of the same - rigidity - inability to stay still and / or sit with the will to move continuously - uncontrolled movements of the mouth, tongue and facial muscles - tremors.

These effects occur mainly after prolonged treatments, especially if you are elderly.

The side effects listed below are listed according to how often they occur.

Very common (affects 1 in 10 users):

weight gain

Common (affects 1 to 10 users in 100):

rhinitis (inflammation of the nasal passages)
increased appetite
depression
insomnia
drowsiness
constipation
stomach upset
nausea
muscle aches
menstrual irregularities
breast pain
fatigue

Uncommon (affects 1 to 10 users in 1000):

depressive symptoms
sleep disorders
anxiety
apathy
abnormalities of coordination of movements
disorientation
lethargy (deep sleep)
tingling in the legs and arms or other parts of the body, numbness, feeling hot or cold
restlessness
indolence (listlessness)
tinnitus (ringing in the ears)
stiff neck
palpitations (sensations of increased heartbeat)
hypotension (low blood pressure)
intestinal obstruction
dry mouth
gastrointestinal upset (stomach ache or other digestive problems)
excessive sweating
muscle spasms and / or contractions
menorrhagia (profuse and abnormal blood loss during menstruation)
menstrual disturbances (excessive increase in menstrual flow)
oligomenorrhea (alteration and shortage of menstrual flow)
excessive development of the breasts (large breasts)
decreased sexual desire
swelling that may affect the hands and feet (peripheral edema) or multiple parts of the body (generalized edema)
asthenia (tiredness)

Not known (the frequency of which cannot be estimated from the available data):

inability to sit up
pathological slowness of movements
cogwheel stiffness (if when moving an arm it appears that the elbow has a cogwheel so it jerks)
abnormal and involuntary movement of the muscles of the body
extrapyramidal disorders (rigidity, tremor) and parkinsonism
sedation
tremor
increase in liver enzymes (transaminases) which can lead to changes in some clinical tests
erythema (skin irritation)
muscle stiffness
galactorrhea (abnormal milk secretion in women who are not breastfeeding)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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

5 mg capsule: store below 25 ° C.

10 mg capsule: this medicine does not require any special storage conditions

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

Do not use this medicine if you notice changes in the color of the capsule.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Gradient Polifarma contains

5 mg capsule

the active substance is: flunarizine dihydrochloride (1 capsule contains 5.9 mg of flunarizine dihydrochloride equal to 5 mg of flunarizine base)
the other ingredients are: anhydrous lactose (see section "Gradient Polifarma contains lactose"), corn starch, magnesium stearate, titanium dioxide, gelatin.

10 mg capsule

the active substance is: flunarizine dihydrochloride (1 capsule contains 11.8 mg of flunarizine dihydrochloride equal to 10 mg of flunarizine base)
the other ingredients are: anhydrous lactose (see section "Gradient Polifarma contains lactose"), corn starch, magnesium stearate, titanium dioxide, gelatin.

Description of the appearance of Gradient Polifarma and contents of the package C

Hard capsules

Gradient Polifarma 5 mg: carton containing 50 hard capsules packed in five blisters of 10 capsules of white opaque color

Gradient Polifarma 10 mg: carton containing 50 hard capsules packed in five blisters of 10 capsules of white opaque color.

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.

Further information on Gradient Polifarma is available in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on the ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

GRADIENT POLIFARMA RIGID CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

GRADIENT POLIFARMA 5 mg hard capsules

One hard capsule contains: active ingredient: flunarizine dihydrochloride 5.9 mg (equivalent to 5 mg of flunarizine base).

GRADIENT POLIFARMA 10 mg hard capsules

One hard capsule contains: active ingredient flunarizine dihydrochloride 11.8 mg (equivalent to 10 mg of flunarizine base).

Excipient with known effect: lactose

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

5 mg hard capsules

10 mg hard capsules

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Prophylactic treatment of migraine with frequent and severe attacks limited to patients who have not responded to other therapies or in whom these therapies have caused serious side effects.

04.2 Posology and method of administration

Attack therapy

In patients under the age of 65, treatment should be started at a dose of 10 mg per day to be taken at bedtime; in patients over the age of 65 this dosage should be reduced to 5 mg.

If depression, extrapyramidal signs or other serious side effects appear during this phase of treatment, the treatment should be discontinued.

If no significant improvement is observed after two months, patients should be considered refractory to therapy and drug administration discontinued.

Maintenance therapy

If the patient responds satisfactorily and maintenance therapy is deemed necessary, the daily dose should be reduced and administered every other day or for 5 consecutive days with a two-day interruption each week.

Even if the prophylactic treatment is effective and well tolerated, it must be stopped after six months and can only be resumed in case of relapse.

04.3 Contraindications

Flunarizine is contraindicated in patients with ongoing depressive illness or with a history of recurrent depression (see sections 4.4 and 4.8).

Flunarizine is contraindicated in patients with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders (see sections 4.4 and 4.8).

Flunarizine is contraindicated in patients with known hypersensitivity to flunarizine or to any of the excipients contained in the composition.

04.4 Special warnings and appropriate precautions for use

Flunarizine can give rise to extrapyramidal and depressive symptoms with manifesting parkinsonism, especially in elderly patients. Therefore, it should be used with caution in such patients.

It is recommended not to exceed the recommended doses. Patients should be monitored at regular intervals, especially during maintenance therapy, to look for the first extrapyramidal or depressive signs in order to stop treatment promptly.

In rare cases, fatigue may progressively increase during therapy with flunarizine: in this case, therapy should be discontinued.

Any loss of drug efficacy during the maintenance phase requires discontinuation of therapy (for the duration of treatment see section 4.2).

Important information about some of the ingredients

Lactose

Flunarizine capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

The concomitant intake of alcohol, hypnotics, or tranquilizers with flunarizine can cause excessive sedation.

The pharmacokinetics of flunarizine are not affected by topiramate. Following repeated dosing to migraine patients, the systemic exposure to flunarizine was increased by 14%. When flunarizine was administered concomitantly with topiramate 50 mg every 12 hours, administration of repeated doses resulted in a 16% increase in exposure. systemic to flunarizine. Steady state pharmacokinetics of topiramate are unaffected by flunarizine.

Chronic administration of flunarizine had no effect on the availability of phenytoin, carbamazepine, valproate or phenobarbital. Plasma concentrations of flunarizine were generally lower in patients with epilepsy taking these anti-epileptic drugs (AEDs) compared to healthy subjects given similar doses. The plasma protein binding of carbamazepine, valproate and phenytoin is not affected by concomitant administration of flunarizine.

04.6 Pregnancy and lactation

Pregnancy

There are no data on the use of flunarizine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of flunarizine during pregnancy.

Feeding time

It is not known whether flunarizine is excreted in human milk. Animal studies have shown excretion of flunarizine in breast milk.

A decision to discontinue breast-feeding or to continue / discontinue flunarizine therapy must be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

04.7 Effects on ability to drive and use machines

As somnolence may occur, especially at the initiation of treatment, caution should be exercised during activities such as driving vehicles or operating hazardous machinery.

04.8 Undesirable effects

The safety of flunarizine was evaluated in 247 flunarizine-treated subjects who participated in two placebo-controlled clinical trials in the treatment of dizziness and migraine, respectively, and in 476 flunarizine-treated subjects who participated in two controlled clinical trials with comparator in the treatment of dizziness and / or migraine. Based on the safety data collected from these clinical studies, the most commonly reported undesirable effects (incidence ≥ 4%) were (% incidence): weight gain (11% ), sleepiness (9%), depression (5%), increased appetite (4%), and rhinitis (4%).

The table below lists the ADRs, including the adverse reactions mentioned above, that have been reported with the use of flunarizine in both clinical trials and post-marketing.

Side effects are listed by frequency using the following convention:

Very common (≥1 / 10); common (≥1 / 100 y

Organic System Classification Adverse Drug Reactions Frequency class Very Common (≥1 / 10) Common (≥1 / 100 y Uncommon (≥1 / 1,000 y Not known Infections and Infestations Rhinitis Metabolism and nutrition disorders Increased Appetite Psychiatric disorders Depression; Insomnia Depressive Symptoms; Sleep disorders; Anxiety, Apathy Pathologies of the Nervous System Drowsiness Coordination anomalies; Disorientation, Lethargy; Paresthesia; Restlessness Indolence; Tinnitus; Stiff neck Akathisia, Bradykinesia, Cogwheel stiffness; Dyskinesia; Essential tremor; Extrapyramidal Disorders; Parkinsonism; Sedation; Tremor Cardiac pathologies Palpitations Vascular pathologies Hypotension Hepatobiliary disorders Increased hepatic transaminases Gastrointestinal disorders Constipation; Upset stomach; Nausea Intestinal obstruction; Dry mouth Gastrointestinal disorders Skin and Subcutaneous Tissue Disorders Hyperhidrosis Erythema Musculoskeletal and Connective Tissue Disorders Myalgia Muscle spasms Muscle contractions Muscle stiffness Diseases of the reproductive system and breast Menstrual irregularities; Breast pain Menorrhagia; Menstrual disturbances; Oligomenorrhea, Breast hypertrophy; Decreased libido Galactorrhea General disorders and administration site conditions Fatigue Generalized edema; Peripheral edema; Asthenia Diagnostic tests Weight gain

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows for continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the reporting system. address http://www.agenziafarmaco.gov.it/it/responsabili

04.9 Overdose

Sedation, agitation and tachycardia have been observed in reported cases of acute overdose (up to 600 mg in a single intake).

Treatment of acute overdose consists of administration of charcoal, induction of vomiting or gastric lavage, and supportive measures.

A specific antidote is not known.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

PHARMACOTHERAPEUTIC CATEGORY: Antivertigo preparations

ATC CODE: N07CA03.

Flunarizine is a bifluorinated derivative of cinnarizine with antihistamine and CNS depressant properties.

Flunarizine is a WHO class IV calcium channel blocker; it has no effect on contractility and cardiac conduction.

Flunarizine also possesses a "neuroleptic type action which could be the cause of certain side effects on the central nervous system.

05.2 "Pharmacokinetic properties

In healthy volunteers, peak plasma is reached after 2-4 hours following oral administration of a single dose of Flunarizine. During chronic treatment, for administration of a daily dose of 10 mg, plasma concentrations gradually increase, until the steady state concentration is reached around the 5th-6th week of drug intake: at steady-state, plasma levels remain almost constant over a range between 39 and 115 ng / ml.

The pharmacokinetic parameters of Flunarizine are characterized by a large volume of distribution (apparent volume of distribution = 43.2 l / kg in healthy volunteers) and by a high tissue distribution.

In fact, from the results of animal experiments, it emerged that drug concentrations in various tissues are much higher than the corresponding plasma levels, especially in adipose tissue and skeletal muscles.

Approximately 0.8% of Flunarizine is present in free plasma, as it binds 90% to plasma proteins and 9% to erythrocytes.

Only a negligible portion of the drug is excreted unchanged in the urine. After extensive hepatic metabolism (dealkylation - N-oxidative, aromatic hydroxylation and glucuronidation), flunarizine and its metabolites are excreted with the faeces via the bile.

In the "man" the mean terminal elimination half-life is about 18 days.

05.3 Preclinical safety data

Toxicity

For acute administration

LD50 Topo Swiss, per os: 815 mg / Kg

DL50 Topo Swiss, for ip: 174 mg / Kg

LD50 Rat S.D., per os: 312 mg / Kg

LD50 Rat S.D., for ip: 353 mg / Kg

For prolonged administration

S.D. rat, per os (18 months) weight decrease to 80 mg / kg / day.

Beagle dog, per os (12 months) no alteration at 20 mg / kg / day.

Fetal toxicity

Absent (Ratte S.D., Coniglio N.Z.).

Flunarizine has no chemical analogy with compounds recognized as carcinogens and cocarcinogens; in the prolonged administration tests (rat and dog) there were no histological manifestations or any suspected biochemical activities.