Active ingredients: Mefloquine (mefloquine hydrochloride)
Lariam 250 mg tablets
Indications Why is Lariam used? What is it for?
Lariam contains the active substance mefloquine hydrochloride, a medicine that belongs to a group of medicines called antimalarials.
Malaria is a disease that is spread through the bite of an infected mosquito that transmits the malaria parasite into the bloodstream.
Lariam is indicated:
- for the prevention and treatment of malaria caused by strains of P. falciparum that infect humans, including those resistant to other antimalarials. In cases of malaria caused simultaneously by strains of P. falciparum and P. vivax, after therapy with Lariam , in order to also eliminate the hepatic forms of P. vivax, the doctor will consider a treatment with an 8-aminoquinoline derivative such as primachine. When prescribing antimalarial medicines, the doctor will take into consideration the instructions issued by the Ministry of Health in accordance with the provisions by the WHO (World Health Organization);
- for the self-treatment of malaria, the doctor can prescribe Lariam in case of trips to areas at risk to be taken as an emergency measure in cases of suspected malaria, when a prompt medical opinion is not available.
Contraindications When Lariam should not be used
Do not take Lariam
- if you are allergic to mefloquine, chemically closely related substances (e.g. quinine, quinidine) or any of the other ingredients of this medicine (listed in section 6)
- for the purpose of malaria prevention, if you suffer from depression (or have suffered from it in the past), or other mental disorders and diseases such as generalized anxiety, psychosis, suicidal intentions or attempts, self-harming behavior, schizophrenia or other disorders psychiatric
- if you suffer or have suffered in the past from seizures characterized by uncontrolled body movements (convulsions) of any origin (see sections "Warnings and precautions" and "Other medicines and Lariam")
- if you have suffered in the past from hemoglobinuric fever, a complication of malaria caused by a particular strain of parasites (Plasmodium falcifarum) characterized by a massive breakdown of red blood cells (intravascular hemolysis) which causes loss of hemoglobin, the protein that carries oxygen to the blood, through the urine (hemoglobinuria)
- if you suffer from severe liver disease (see sections "Warnings and precautions" and "Possible side effects")
- during pregnancy and breastfeeding (see "Pregnancy and breastfeeding").
Another medicine, called halofantrine, should not be used during prevention with Lariam or during treatment of malaria or within 15 weeks of taking the last dose of Lariam, due to the risk of life-threatening heart effects (i.e. changes known as prolongation of the "QTc interval" (see sections "Warnings and precautions" and "Other medicines and Lariam").
Precautions for use What you need to know before taking Lariam
Talk to your doctor or pharmacist before taking Lariam.
Children and adolescents
Experience with the use of Lariam in children weighing less than 5 kg or less than 3 months of age is limited.
Your doctor will take special care if you suffer from:
- epilepsy, because with this medicine you may increase the risk of seizures (see "Possible side effects" and "Other medicines and Lariam"). Your doctor will prescribe Lariam only as a therapy (not for self-treatment) and only in the presence of valid medical reasons for using the drug;
- liver disease, because it has a higher risk of experiencing side effects;
- kidney diseases;
- congenital hyperinsulinemic hypoglycaemia, a hereditary disease causing low blood glucose levels due to high insulin production, because you are at risk of developing hypoglycaemia with this medicine;
- diabetes and take other medications (blood thinners);
- diseases related to the blood and lymphatic system (set of organs and tissues in which the production of the corpuscular elements of the blood occurs: red blood cells, white blood cells and platelets).
Side effects
During treatment with this medicine you may experience side effects that may require you to stop treatment (see section 4 "Possible side effects").
Prolonged use
If you need to be treated with Lariam for an extended period (more than 1 year), your doctor will need to monitor your health closely and ask you to undergo laboratory tests, including liver function tests and blood tests. eyes.
Geographical resistance to drugs
Some geographical areas, especially the areas of South East Asia, are more prone to the presence of parasites resistant to antimalarial drugs. This may require a different malaria prevention based on the geographical area in which you intend to go. For up-to-date information on resistance in different geographic areas, consult competent centers with national experts. In addition, in some geographical areas there may be mixed forms of malaria, in this case the doctor will prescribe other antimalarial medicines (eg primachine) together with the preventive therapy with Lariam.
Interactions Which drugs or foods can modify the effect of Lariam
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, especially:
- halofantrine (another antimalarial medicine): the use of halofantrine during therapy with mefloquine for the prevention or treatment of malaria or in the 15 weeks following the last dose of Lariam causes undesirable effects in the heart (prolongation of the interval QTc) (see section "What you need to know before you take Lariam");
- other drugs capable of modifying cardiac conduction (eg: antiarrhythmics, beta-blockers, calcium channel blockers, antihistamines or H1-antagonists, tricyclic antidepressants and phenothiazines): concomitant use of these drugs may contribute to the effects on the heart;
- ketoconazole (an antifungal medicine), due to the risk of heart effects (prolongation of the QTc interval), if taken during therapy with Lariam or within 15 weeks after the last dose of Lariam (see section "Warnings and precautions ");
- anticonvulsants and drugs that lower the threshold that generates seizures (eg. valproic acid, carbamazepine, phenobarbital or phenytoin): concomitant use of Lariam reduces the control of seizures therefore in some cases the doctor may deem it necessary to change the doses of antiepileptic drugs;
Concomitant administration of mefloquine and medicinal products that work by lowering the threshold that generates seizures (such as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), bupropion, antipsychotics, tramadol, chloroquine or some antibiotics) may increase the risk of seizures (see paragraph "Warnings and precautions");
- vaccines: when Lariam is taken at the same time or shortly before oral typhoid vaccines, it is possible that there may be an attenuation of the immune response induced by these vaccines. Therefore the typhoid vaccination must be completed at least 3 days before taking the first dose of Lariam bearing in mind that prevention with Lariam must begin 10 days before arriving in a malarial area;
- other interactions / inhibitors and inducers of CYP3A4: Mefloquine is unlikely to modify the metabolism of concomitantly administered drugs. However, there are some medicines, called inducers (rifampicin, carbamazepine, phenytoin, efavirenz) or inhibitors (ketoconazole) of the CYP3A4 isoenzyme, which can cause a decrease or increase in the concentration of mefloquine in the blood. close clinical monitoring is known and must be ensured (see section "Precautions for use");
- anticoagulants: if you take anticoagulants you must be checked before leaving for a malarial area.
Do not take Lariam if you are already taking quinine or chemically related substances (eg quinidine, chloroquine, quinolones) which can cause changes in the electrocardiograph and increase the risk of seizures (see "How to take Lariam") .
Lariam with food, drink and alcohol
Take Lariam preferably after a meal (see section 3 "How to take Lariam").
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
Do not use Lariam during pregnancy (see section "Do not take Lariam"), unless your doctor decides that your medical condition requires treatment with mefloquine. In the event of an unexpected pregnancy, taking Lariam for malaria chemoprophylaxis is not an "indication for termination of pregnancy."
Feeding time
Do not use Lariam if you are breastfeeding (see section "Do not take Lariam").
Driving and using machines
Some undesirable effects such as feelings of instability, alterations in the sense of balance or disturbances affecting the central or peripheral nervous system, can decrease the ability to concentrate and react and, therefore, constitute a risk in case you drive vehicles (including bicycle), use machinery or any other activity that requires a good state of vigilance and coordination of motor activity.
In a limited number of patients it is possible that dizziness or vertigo and loss of balance may continue for a few months or more even after stopping the medicine (see section "Possible side effects").
Lariam contains lactose (milk sugar)
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 Lariam: Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Take Lariam tablets whole with at least one glass of liquid and preferably after a meal. You can break and / or dissolve the tablets in some water, milk or other beverage for administration to younger children or if you have difficulty swallowing.
Malaria therapy
The recommended dose varies according to body weight and immune status (if you have already developed antibodies to malaria).
Your doctor may instruct you to divide the dose into 2-3 administrations with an interval of 6-8 hours to reduce possible side effects.
For body weight less than 20 kg:
Splitting the dose into 2-3 administrations with an interval of 6-8 hours (e.g. 3 + 1 or 3 + 2 or 3 + 2 + 1 tablets) can reduce the frequency or severity of side effects.
For body weight over 60 kg:
There is no specific experience with overall doses higher than 6 tablets in very heavy weight patients.
If you vomit:
- within 30 minutes of taking the medicine, take a second full dose;
- 30-60 minutes after taking the medicine, take half the dose.
Malaria prevention
The recommended dose varies according to body weight and is approximately 5 mg / kg to be taken once a week.
Initial dose
Your doctor will recommend that you take the first dose 10 days before departure and the second dose 3 days before departure.
Subsequent doses
Take subsequent doses once a week on the same day all the time.
If this is not possible, a loading dose should be administered: in the case of adults weighing more than 45 kg this corresponds to 1 tablet of Lariam per day (250 mg of mefloquine) for 3 days, followed by 1 tablet per week.
In order to reduce the risk of malaria, prevention must be continued for a further 4 weeks after departure from the endemic area.
Self-treatment of malaria
The recommended starting dose varies according to body weight and is approximately 15 mg / kg (e.g. in patients weighing 45 kg or more, the starting dose will be 3 Lariam tablets).
Subsequent doses
If you do not have medical assistance within 24 hours or if no serious side effects have occurred, a second fraction of the total dose (2 tablets in patients weighing 45 kg or more) can be taken 6-8 hours later.
Patients weighing more than 60 kg will need to take another tablet 6-8 hours after the second dose (see previously recommended regimen for the treatment of malaria).
Use in children and adolescents
Experience with the use of Lariam in children weighing less than 5 kg or less than 3 months of age is limited.
If you forget to take Lariam
Do not take a double dose to make up for a forgotten dose.
If you stop taking Lariam
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Lariam
In case of accidental ingestion / intake of an excessive dose of Lariam, notify your doctor immediately or go to the nearest hospital.
Symptoms
If you take more Lariam than you should, there may be an "intensification of the side effects described in the section" Possible side effects ".
Treatment
The doctor will establish adequate therapy to treat the symptoms. There are no specific antidotes, for example it is possible to use activated charcoal orally which reduces the absorption of mefloquine.
Side Effects What are the side effects of Lariam
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any side effects while taking Lariam, please inform your doctor immediately who will decide whether to stop the treatment and prescribe an alternative medicine.
Mefloquine can induce:
- symptoms affecting mental status, such as abnormal dreams, insomnia, depression, anxiety, suicide, suicide intention and attempt, self-harming behavior, alternating depressed and euphoric mood (bipolar disorder), mental (psychotic) disturbance of various types, including delirium, depersonalization, mania and schizophrenia / schizophreniform disorder, paranoia, panic attacks, confusion, hallucinations, aggression, agitation, restlessness, mood swings, attention disturbances. These side effects occur especially during preventive use of Lariam. They may appear even after stopping the medicine or persist for months or more even after stopping the medicine.
- nerve pain symptoms such as dizziness, headache, nerve pain symptoms such as brain disease (encephalopathy), cranial nerve palsy, uncontrolled body movement (seizures), memory loss (sometimes long lasting even for more than 3 months), syncope, speech disturbances, memory loss, balance disturbances, gait disturbances, sleepiness. These side effects occur especially during preventive use of Lariam. They may appear even after stopping the medicine or persist for months or more even after stopping the medicine.
- suffering of the nerves responsible for peripheral sensitivity (neuropathy), including pain, burning, tingling, numbness and / or weakness; suffering of the nerves responsible for movement, including impaired sensation in the limbs or other parts of the body (paraesthesia), tremor and difficulty in performing certain movements (ataxia).
- eye disease, optic nerve pain and retinal disorders (may occur during or after treatment with Lariam).
- allergic reactions, reported more frequently in predisposed subjects, which can manifest themselves in various ways, eg. mild to severe skin reactions with rapid onset (anaphylactic reactions and Stevens-Johnson syndrome).
- heart symptoms, such as changes in heart rhythm (including tachycardia or bradycardia) or perception of your heart beating (palpitations), irregular heartbeat, extrasystoles, because these symptoms may precede side effects, even serious, at the level of the heart. heart as transient disturbances in the electrical conduction system of the heart, such as atrioventricular block.
- symptoms of pneumonia, such as difficulty in breathing (dyspnoea), dry cough or fever, which may be a sign of pneumonia that may be allergic to you.
The possible side effects observed after the marketing of Lariam and in a study involving a number of patients are listed below according to frequency:
Very common (may affect more than 1 in 10 patients)
- abnormal dreams, insomnia.
Common (may affect up to 1 in 10 patients)
- depression, anxiety;
- dizziness, headache;
- weakening of vision (visual impairment);
- nausea, vomiting. These side effects occur especially during preventive use of Lariam. They are generally mild in intensity and may decrease with prolonged use of the medicine;
- diarrhea, pain in the abdomen, mouth lesions;
- itch.
Not known (frequency cannot be estimated from the available data)
- decrease in the number of white blood cells in the blood (leukopenia), especially granulocytes (agranulocytosis), insufficient production of blood cells in the bone marrow (aplastic anemia), increase in the number of white blood cells in the blood (leukocytosis), decrease in the number of platelets in the blood (thrombocytopenia);
- decreased appetite;
- symptoms of nervous system distress such as brain disease (encephalopathy), paralysis of the nerves of the skull, uncontrolled body movements (seizures), memory loss (sometimes lasting for more than 3 months), syncope, speech disturbances, lack of memory, balance disturbances, gait disturbances, sleepiness;
- suffering of the nerves responsible for peripheral sensitivity (peripheral sensory neuropathy), suffering of the nerves responsible for movement (peripheral motor neuropathy);
- loss of transparency of the natural lens of the eye (cataract) and blurred vision. These side effects may occur during or after treatment with Lariam;
- disturbed balance, ringing in the ears (tinnitus), partial (sometimes prolonged) deafness, hearing problems, increased sensitivity to sound (hyperacusis);
- decrease (hypotension) or increase (hypertension) in blood pressure, hot flashes;
- inflammation of the pancreas (pancreatitis), discomfort in the upper abdomen (dyspepsia);
- impaired liver function, inflammation of the liver (hepatitis), yellowing of the skin (jaundice), transient increase in enzymes produced by the liver (transaminases) shown in blood tests (ALT, AST, GGT);
- pneumonia pneumonia possibly allergic in nature, difficulty in breathing (dyspnoea);
- severe skin rash (Stevens-Johnson syndrome), red lesions (erythema multiforme), skin rash (rash), skin irritation (erythema), red or white hives of various sizes (hives) loss hair and hair (alopecia), excessive sweating (hyperhidrosis);
- muscle weakness, muscle cramps, muscle and joint pain;
- edema, chest pain, lack of strength (asthenia), malaise, tiredness, chills, fever;
- impaired kidney function (acute kidney failure), inflammation of the kidneys (nephritis), increased blood creatinine;
- heart symptoms, such as changes in heart rhythm (including tachycardia or bradycardia) or perception of your heart beating (palpitations), irregular heartbeat, extrasystoles;
- symptoms affecting mental status, such as suicide, suicide intention and attempt, self-harming behavior, alternating depressed and euphoric moods (bipolar disorders), various types of (psychotic) mental status disorders, including delirium, depersonalization, mania and schizophrenia / schizophreniform disorder, paranoia, panic attacks, confusion, aggression, agitation, restlessness, mood swings, attention disorders.
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 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
Store in the original package to protect from moisture.
Keep this medicine out of the sight and reach of children.
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 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.
Deadline "> Other information
What Lariam contains
One tablet contains:
- The active ingredient is mefloquine hydrochloride 274.09 mg (equivalent to mefloquine base 250 mg).
- The other ingredients are microcrystalline cellulose, lactose (see section "Lariam contains lactose"), crospovidone, maize starch, ammonium-calcium alginate, poloxamer, talc, magnesium stearate.
What Lariam looks like and contents of the pack
Lariam comes as white tablets contained in blisters.
Lariam is available in packs of 8 tablets of 250 mg.
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 -
LARIAM 250 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One tablet contains:
active ingredient: mefloquine hydrochloride 274.09 mg (equal to mefloquine base 250 mg).
For the full list of excipients, see 6.1.
03.0 PHARMACEUTICAL FORM -
Tablets.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Malaria therapy and prophylaxis
Mefloquine is indicated for the therapy and prophylaxis of malaria in particular caused by strains of P. falciparum which are resistant to other antimalarials.
In cases of malaria caused by strains of P. falciparum and P. vivax simultaneously, after therapy with Lariam, in order to also eliminate the hepatic forms of P. vivax, it is necessary to consider a treatment with an 8-aminoquinoline derivative such as primachine.
When prescribing antimalarial drugs it is recommended to take into consideration the instructions issued by the Ministry of Health in accordance with the provisions of the "O.M.S.
Reserve treatment
Lariam can also be prescribed to travelers as a self-treatment to be taken as an emergency measure in cases of suspected malaria, when prompt medical advice is not available.
04.2 Posology and method of administration -
The tablets should be swallowed whole with at least one glass of liquid and preferably after a meal. The tablets can be divided and dissolved in a little water, milk or other beverage for administration to younger children or people with swallowing difficulties.
The use of a loading dose may be associated with an increase in adverse events.
When mefloquine chemoprophylaxis fails, the physician must carefully consider which antimalarial to use for therapy. For the use of halofantrine see sections 4.3, 4.4 and 4.5.
Malaria therapy
The recommended total therapeutic dose in non-immune patients is 20-25 mg / kg. A dose of 15 mg / kg may be sufficient for partially immune individuals. Therefore the total dose of mefloquine for adults and non-immune children weighing more than 45 kg is 1250-1500 mg (e.g. 5-6 tablets of Lariam). A lower total dose of 750-1000 mg is sufficient for patients of the same weight living in malarial areas as they are partially immune.
Recommended dosage of Lariam according to body weight and immune status: total therapeutic dose *.
* If the total therapeutic dose is divided into 2-3 administrations with an interval of 6-8 hours (eg: 3 + 1 or 3 + 2 or 3 + 2 + 1 tablets) it is possible to reduce the incidence or severity of the effects collateral.
** Experience with Lariam in children less than 3 months of age or weighing less than 5 kg is limited.
*** There is no specific experience with overall dosages higher than 6 tablets in very heavy weight patients.
Patients who vomit within 30 minutes of drug administration should be given a second full dose. In the event that vomiting occurs 30-60 minutes after taking the drug, administration of half the dose is indicated.
In the event that a full course of Lariam therapy has not led to improvement within 48-72 hours, an alternative treatment should be used.
Similarly, if previous mefloquine prophylaxis has not proved effective, Lariam should not be used for therapy. For the use of other antimalarials see the sections "Interactions" and "Special warnings and appropriate precautions for use".
In areas characterized by multidrug-resistant malaria it is possible to resort, if available, to an initial treatment with artemisin or its derivative, followed by the administration of Lariam.
Patients should not be unaware that reinfection or recurrence can occur despite effective antimalarial treatment.
Malaria prophylaxis
The recommended prophylactic dose of Lariam is approximately 5 mg / kg once a week.
In order to ensure, prior to arrival in the endemic area, that the administration of Lariam is well tolerated, it is recommended to start chemoprophylaxis with Lariam 10 days before departure (ie take the first intake 10 days before departure and the second 3 days before departure) Subsequent doses should be taken once a week (on a fixed day). If this is not possible, a loading dose should be administered: in the case of adults weighing more than 45 kg this corresponds to one tablet of Lariam per day (250 mg of mefloquine) for three days, followed by a weekly tablet. In the event that the traveler is taking other drugs, it may be indicated to start prophylaxis 2-3 weeks before departure in order to ensure that the drug combination is well tolerated (see section 4.5). In order to reduce the risk of malaria, prophylaxis must be continued for a further four weeks after departure from the endemic area.
1. Adults and children weighing more than 45 kg
In adults and children weighing more than 45 kg, the prophylactic dose of mefloquine is 250 mg (1 tablet of Lariam) to be taken once a week.
2. Adults and children weighing less than 45 kg
The weekly dose decreases in proportion to body weight:
less than 20 kg: ¼ tablet
between 20 and 30 kg: ½ tablet
more than 30-45 kg: ¾ tablet
Experience with Lariam in children weighing less than 5 kg or less than 3 months of age is limited.
3. Elderly
No specific dosage adjustment is required for the elderly. See the sections "Contraindications", "Interactions" and "Special warnings and appropriate precautions for" use.
Reserve treatment
Lariam can be prescribed for use in self-administration in cases where it is not possible to promptly consult a doctor. Self-medication should be started with a dose of about 15 mg / kg; in patients weighing 45 kg or more, the starting dose will therefore be three Lariam tablets. If professional medical assistance cannot be obtained within 24 hours or if serious side effects have not occurred, a second fraction of the total dose (2 tablets in patients weighing 45 kg or more) can be taken 6-8 hours later. Patients weighing more than 60 kg will need to take another tablet 6-8 hours after the second dose (see previously recommended therapy regimen for therapy).
04.3 Contraindications -
• Known hypersensitivity to mefloquine or related compounds (eg quinine, quinidine), or to any of the excipients contained in the formulation, listed in section 6.1.
• Chemoprophylaxis in patients with active depression, a history of depression, generalized anxiety disorder, psychosis, suicide attempts, suicidal ideation and self-injurious behavior, schizophrenia or other psychiatric disorders, or with a history of seizures of any origin (see sections 4.4 and 4.5).
• Halofantrine should not be used during chemoprophylaxis with Lariam or during treatment of malaria or within 15 weeks of taking the last dose of Lariam, due to the risk of potentially fatal QTc interval prolongation (see sections 4.4 and 4.5).
• In patients with a history of hemoglobinuric fever, a complication of P. falciparum malaria with massive intravascular hemolysis causing hemoglobinuria.
• In patients with severe hepatic impairment (see sections 4.4 and 4.8).
• Generally contraindicated during pregnancy.
04.4 Special warnings and appropriate precautions for use -
Adverse reactions of a neuropsychiatric nature
Mefloquine can induce psychiatric symptoms such as anxiety disorder, paranoia, depression, hallucinations and psychosis. Psychiatric symptoms such as abnormal dreams / nightmares, acute anxiety, depression, restlessness or confusion should be considered prodromal for more serious events (see section 4.8). Cases of suicide, suicidal thoughts, self-harm and suicide attempt have been reported (see section 4.8).
Patients being treated with mefloquine for antimalarial chemoprophylaxis should be advised that if these reactions or changes in mental status occur during the use of mefloquine, it is necessary to stop taking the drug and seek medical advice immediately in order to replace mefloquine with another malaria prevention drug.
If acute attacks of anxiety, depression, restlessness or confusion occur during prophylaxis, Lariam should be discontinued and an alternative medicine prescribed. Adverse reactions to Lariam can also arise after discontinuation of the drug.
Neuropsychiatric reactions (eg, depression, episodes of dizziness or dizziness and loss of balance) have been reported in a small number of patients and may persist for months or longer, even after discontinuation of the drug.
To minimize the risk of these adverse reactions, mefloquine should not be taken for chemoprophylaxis in patients with active psychiatric illness or a history of psychiatric disorders such as depression, anxiety disorders, schizophrenia or psychiatric disorders (see section 4.3).
Hypersensitivity :
Hypersensitivity reactions ranging from mild skin manifestations to anaphylaxis may occur (see section 4.8).
Cardiac toxicity
Concomitant administration of mefloquine and related compounds (e.g. quinine, quinidine, and chloroquine) may induce electrocardiographic abnormalities.
Due to the risk of QTc interval prolongation which can be fatal, halofantrine should not be given during therapy with Lariam for prophylaxis or treatment of malaria or for 15 weeks after taking the last dose of Lariam (see section 5.2).
Due to increased plasma concentrations and the elimination half-life of mefloquine following co-administration with ketoconazole, the risk of QTc interval prolongation can also be anticipated if ketoconazole is taken during therapy with Lariam for prophylaxis or treatment of malaria or within 15 weeks of taking the last dose of Lariam (see sections 4.5 and 5.2).
If arrhythmia or palpitations occur during chemoprophylaxis with Lariam, patients should consult a physician. These symptoms may in rare cases precede serious cardiological undesirable effects.
Convulsive disorders
In epileptic patients mefloquine may increase the risk of seizures, therefore, in these patients, it is recommended to prescribe mefloquine only as a therapy (not for presumptive self-treatment) and only in the presence of valid medical reasons for the use of the drug (see paragraphs 4.3 and 4.5).
Concomitant administration of mefloquine and anticonvulsant drugs (e.g. valproic acid, carbamazepine, phenobarbital or phenytoin) may reduce seizure control as plasma levels of anticonvulsants are reduced. Therefore, patients concomitantly taking antiepileptic drugs including valproic acid, carbamazepine, phenobarbital and phenytoin with mefloquine should monitor plasma levels of antiepileptics and consider dose adjustments if necessary.
Concomitant administration of Lariam and drugs known to lower the seizure threshold (such as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), bupropion, antipsychotics, tramadol, chloroquine or some antibiotics) may increase the risk of seizures (see section 4.5) .
Neuropathy
Cases of polyneuropathy have been reported in patients treated with Lariam (based on neurological symptoms such as pain, burning, sensory disturbances, or muscle weakness, alone or in combination).
Lariam should be discontinued in patients experiencing symptoms of neuropathy such as pain, burning, tingling, numbness and / or weakness to prevent the development of an irreversible condition (see section 4.8).
Eye disorders
Certain eye disorders, including but not limited to optic neuropathies and retinal disorders, have been reported during treatment with mefloquine (see section 4.8). All patients with impaired vision should seek medical attention as some manifestations (such as retinal disorders or optic neuropathy) may require discontinuation of Lariam treatment.
Impaired liver function
In patients with impaired hepatic function the elimination time of mefloquine may be lengthened, therefore the plasma levels of the drug may be higher and there is a higher risk of adverse events.
Renal impairment
Due to limited data, Lariam should be administered with caution to patients with renal impairment.
Pneumonia
Pneumonia of possible allergic aetiology has been reported in patients treated with Lariam (see section 4.8). Patients who develop symptoms of dyspnoea, dry cough or fever while taking Lariam should contact a physician for clinical evaluation.
Disorders of the blood and lymphatic system
Cases of aplastic anemia and agranulocytosis have been reported during treatment with mefloquine (see section 4.8).
CYP3A4 inhibitors and inducers
Inhibitors and inducers of the CYP3A4 isoenzyme may modify the pharmacokinetics / metabolism of mefloquine resulting in an increase or decrease in its plasma concentrations (see section 4.5).
P-glycoprotein substrates and inhibitors
Mefloquine has been shown in vitro to be a substrate and inhibitor of P-glycoprotein. Therefore, it is possible that drug interactions may also occur with drugs that are substrates or whose ability to modify the expression of this transporter is known.The clinical relevance of these interactions is unknown.
Interactions with vaccines
When mefloquine is used in conjunction with live oral anti-typhoid vaccines, a "attenuation of immunization" cannot be ruled out.
Vaccinations with orally administered live bacteria should be completed at least 3 days prior to the first dose of Lariam (see section 4.5).
Long-term use
During clinical trials this drug was not administered for more than a year.
If the drug is to be administered for an extended period, periodic evaluations including liver function tests and ophthalmic examinations should be performed.
Galactose intolerance
Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Geographical resistance to drugs
Geographically distributed resistance may occur for P. Falciparum strains and the appropriate choice of antimalarial prophylaxis may differ from one area to another. P. Falciparum resistance to mefloquine has been reported mainly in multi-resistance areas in Southeast Asia.
In some regions, cross-resistance has been observed between mefloquine and halofantrine and between mefloquine and quinine.
For up-to-date information on geographically distributed resistances, competent centers with national experts should be consulted.
In the presence of mixed forms of malaria, from P. falciparum / P. vivax, therapy with Lariam must be accompanied by relapse prophylaxis with an 8-aminoquinoline derivative (eg primachine), in order to eliminate the intrahepatic forms of P. vivax.
Hypoglycemia
The possibility of hypoglycaemia should be considered in patients with congenital hyperinsulinemic hypoglycemia.
04.5 Interactions with other medicinal products and other forms of interaction -
Lariam should not be administered concomitantly with quinine or related compounds (e.g. quinidine,
chloroquine, quinolones) which may induce the appearance of electrocardiographic changes and increase the risk of convulsions (see section 4.2).
Halofantrine
It was found that the use of halofantrine during therapy with mefloquine for prophylaxis or treatment of malaria or in the 15 weeks following the last dose of mefloquine causes a significant lengthening of the QT interval (see sections 4.3 and 4.4). A clinically significant lengthening of the QT interval was found with mefloquine alone.
Other drugs that lead to a prolongation of the QTc interval
Concomitant administration of drugs capable of modifying cardiac conduction (eg, antiarrhythmics, beta-blockers, calcium channel blockers, antihistamines or H1 antagonists, tricyclic antidepressants and phenothiazines), may contribute to the prolongation of the QT interval.
There are no data that definitively establish whether concomitant administration of mefloquine and the above drugs has an effect on cardiac function.
Due to increased plasma concentrations and the elimination half-life of mefloquine following co-administration with ketoconazole, the risk of QTc interval prolongation may be anticipated if ketoconazole is taken during therapy with Lariam for prophylaxis or treatment of malaria or within 15 weeks following the last dose of Lariam (see sections 4.4 and 5.2).
Anticonvulsants and drugs that lower the seizure threshold
In patients taking anticonvulsant drugs (valproic acid, carbamazepine, phenobarbital or phenytoin), concomitant use of mefloquine reduces seizure control as plasma levels of anticonvulsants are reduced. Therefore, in some cases, adjustment of the levels is necessary. doses of antiepileptic drugs.
Concomitant administration of mefloquine and drugs known to lower the seizure threshold (such as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), bupropion, antipsychotics, tramadol, chloroquine or some antibiotics) may increase the risk of seizures (see section 4.4) .
Other interactions / inhibitors and inducers of CYP3A4
Mefloquine does not inhibit or induce the cytochrome P450 enzyme system. Therefore, the metabolism of drugs administered concomitantly with mefloquine is unlikely to be affected. However, inducers (rifampicin, carbamazepine, phenytoin, efavirenz) or inhibitors (ketoconazole) of the CYP3A4 isoenzyme may modify the pharmacokinetics / metabolism of mefloquine, resulting in a decrease or increase in its plasma concentrations. are known and close clinical monitoring should be warranted (see section 4.4).
Interaction with vaccines
When mefloquine is taken at the same time or shortly before oral anti-typhoid vaccines, an "attenuation of" immunization induced by these vaccines cannot be ruled out. Therefore, the typhoid vaccination should be completed at least 3 days prior to the start of mefloquine administration bearing in mind that mefloquine prophylaxis should begin 10 days before arriving in a malarial area (see section 4.4).
P-glycoprotein substrates and inhibitors
Mefloquine has been shown in vitro to be a substrate and inhibitor of P-glycoprotein. Therefore, it is possible that drug interactions may also occur with drugs which are substrates or which are known to modify the expression of this transporter. The clinical relevance of these interactions is unknown.
No other cases of interactions with other drugs are known. In any case, the effects of Lariam on patients taking other medications, especially diabetics or those using anticoagulants, should be checked before departure.
04.6 Pregnancy and breastfeeding -
Pregnancy
A teratogenic effect was observed in mice and rats and an embryotoxic effect was observed in rabbits; however extensive clinical experience with Lariam used for prophylactic purposes did not reveal teratogenic or embryotoxic effects.
Therefore:
- due to the severity of malaria during pregnancy, women who are pregnant or wishing to become pregnant should be discouraged from traveling to endemic areas. Prophylactic treatment with mefloquine can be considered regardless of the term of pregnancy, but in strict compliance with the indications.
- The use of mefloquine as a curative treatment in pregnant women is limited to the treatment of uncomplicated acute malaria when quinine is contraindicated or in the case of P. falciparum resistant to quinine.
In the event of an unexpected pregnancy, taking Lariam for malaria chemoprophylaxis is not an "indication for termination of pregnancy."
For the use of mefloquine during pregnancy, national and international guidelines should be consulted.
Feeding time
Mefloquine is excreted in breast milk in small amounts whose activity is unknown. As a precautionary measure, mefloquine should be avoided in breastfeeding women.
National and international guidelines should be consulted for the use of mefloquine in breastfeeding women.
04.7 Effects on ability to drive and use machines -
People who, while taking Lariam, experience feelings of instability, alterations in the sense of balance or disturbances affecting the central or peripheral nervous system, must be particularly cautious when driving vehicles, piloting aircraft, operating machinery. , in performing scuba diving or any other activity that requires good alertness and coordination of motor activity. In a limited number of patients it has been reported that dizziness or vertigo and loss of balance may continue for a few months or more even after discontinuation of drug administration (see section 4.8).
04.8 Undesirable effects -
Hypersensitivity reactions may occur in predisposed subjects.
At the doses used for malaria therapy, adverse reactions to Lariam may not be distinguishable from the symptoms of the disease itself.
In chemoprophylaxis, the tolerability profile of mefloquine is characterized by a predominance of neuropsychiatric adverse reactions (see section 4.4). Adverse reactions to Lariam can also arise after discontinuation of the drug.
During chemoprophylaxis with Lariam the most commonly observed reactions are nausea, vomiting and dizziness. Nausea and vomiting are generally mild in intensity and may decrease with prolonged use despite the increase in plasma drug concentration. Neuropsychiatric reactions (eg, depression, episodes of dizziness or dizziness, and loss of balance) may persist for months or more, even after stopping the drug.
Education in vitro and in vivo showed no haemolysis in subjects with glucose-6-phosphate dehydrogenase deficiency.
Post-marketing experience
The table below presents the adverse reactions observed in post marketing and in a randomized double-blind study involving 976 patients (483 patients treated with mefloquine, 493 patients treated with atovaquone / proguanil), in which neuropsychiatric adverse events related to therapy occurred in 139/483 (28.8%) patients treated with mefloquine, compared to 69/493 (14%) patients treated with atovaquone / proguanil. No serious drug-attributable adverse events occurred in either group.
a) Occasionally these symptoms have been reported to persist for a long time after discontinuation of Lariam
b) Description of selected adverse reactions:
Neuropsychiatric adverse reactions
If neuropsychiatric reactions or changes in mental status occur during chemoprophylaxis with Lariam, the patient should stop taking Lariam and consult the physician immediately in order to replace mefloquine with an alternative medicine for the prevention of malaria (see section 4.4). .
Abnormal dreams / nightmares
The onset of abnormal dreams is a very common adverse reaction with mefloquine, therefore their significance should be considered in the overall evaluation of patients reporting reactions or changes in their mental status with mefloquine (see section 4.4).
c) See section 4.4
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili".
04.9 Overdose -
Symptoms
In the event of an overdose of Lariam, the undesirable effects described in section 4.8 may intensify.
Treatment
In the event of an overdose of Lariam, patients should be treated with symptomatic and supportive therapy. There are no specific antidotes. The use of oral activated charcoal to limit the absorption of mefloquine can be considered within one hour of ingestion of the drug taken in overdose. Carefully monitor cardiac activity (if possible with ECG) and neuropsychiatric status for at least 24 hours.
Adequate supportive treatment is also necessary, particularly in the presence of cardiovascular disorders.
The elimination of mefloquine and its metabolites is limited by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: antimalarial.
ATC code: P01BC02.
The efficacy of Lariam in the therapy and prophylaxis of malaria is essentially due to the destruction of the asexual intra erythrocyte forms of the malaria pathogens that infect humans (Plasmodium falciparum, P.vivax, P.malariae, P.ovale).
Lariam is also effective against malaria parasites resistant to other antimalarials such as chloroquine and other 4-aminoquinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulfonamide combinations.
In a randomized, double-blind study, non-immune travelers traveling to a malaria endemic area received malaria prophylaxis with mefloquine (483 subjects) or proguanil and atovaquone. The efficacy of chemoprophylaxis was evaluated as a secondary endpoint. The average travel time was ≈2.5 weeks, and 79% of the subjects went to Africa. 1013 subjects were initially randomized to receive mefloquine (n = 505) or atovaquone-proguanil (n = 508). Thirty-seven subjects gave up for various reasons. Of the 976 subjects who received more than one dose of the drug studied, 966 (99%) completed the study and 963 the follow-up period of 60 days with collection of efficacy data. Although in 10 subjects (5 in each arm of the study) circumsporozoite antibodies were identified, none of them became ill with malaria (minimum efficacy for mefloquine and atovaquone-proguanil was 100%). In general, there were no cases of confirmed malaria in this study (the maximum efficacy for mefloquine and atovaquone-proguanil was 100%). The results indicate that mefloquine and atovaquone-proguanil have similar efficacy for malaria prophylaxis in non-immune travelers (see Table 3).
Table 3 Estimates of minimum and maximum efficacy for malaria prophylaxis
minimum efficacy = 100 x [1 - (n ° of subjects confirmed for malaria / n ° of subjects with circumsporozoite antibodies)]
b maximum efficacy = 100 x [1 - (no. of subjects confirmed for malaria / no. of subjects 60 days of efficacy data)]
05.2 "Pharmacokinetic properties -
Absorption :
The absolute oral bioavailability of mefloquine has not been determined as an intravenous injectable formulation is not available. The bioavailability of the tablets is greater than 85% of that of the oral solution.The presence of food significantly increases both the speed and the extent of absorption, resulting in an increase in bioavailability of approximately 40%.
The maximum plasma concentration after administration of a single oral dose of Lariam is reached in 6-24 hours (median approximately 17 hours). Peak plasma concentration levels expressed in mcg / l are approximately equivalent to the administered dose expressed in milligrams (eg a single dose of 1000 mg results in a maximum concentration of approximately 1000 mcg / l).
With the administration of 250 mg once a week the maximum plasma concentration at steady state (equal to 1000-2000 mcg / l) is reached in 7-10 weeks.
Distribution :
In adults in good health, the apparent volume of distribution is about 20 l / kg, indicating a wide tissue distribution. Mefloquine is able to accumulate inside the erythrocytes that host the parasite at a concentration approximately double that of plasma. 98% of mefloquine is bound to plasma proteins. A blood concentration of 620 ng / ml of mefloquine is considered necessary to achieve a "prophylactic efficacy of 95%." Mefloquine crosses the placenta; excretion into breast milk appears to be minimal (see section 4.6).
Metabolism :
Mefloquine is extensively metabolised in the liver by the cytochrome P450 enzyme system. Studies in vitro And in vivo have clearly indicated that the CYP34A isoenzyme is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The major metabolite, 2,8 bis (trifluoromethyl) 4-quinolin-carboxylic acid, is inactive on P. falciparum. In studies in healthy volunteers, this metabolite appeared in plasma 2 to 4 hours after dose administration. single oral. The maximum plasma concentration of the metabolite, approximately 50% higher than that of mefloquine, was reached after two weeks; thereafter the plasma levels of mefloquine and the main metabolite decrease in similar times. The area under the curve the plasma concentration over time (AUC) of the major metabolite is 3 to 5 times higher than that of the parent drug. The other metabolite, an alcohol, is only found in minimal quantities.
Elimination :
In several studies conducted on healthy adults, the mean half-life of mefloquine is between 2 and 4 weeks (mean 3 weeks). Total clearance, essentially hepatic, is in the order of 30 ml / min. Most of the mefloquine is excreted with the bile and faeces; in volunteers, urinary excretion of unchanged mefloquine and its main metabolite accounted for 9% and 4% of the dose, respectively. It was not possible to measure the concentrations of the other metabolites in urine.
Pharmacokinetics in particular clinical situations :
In children and the elderly the pharmacokinetics of mefloquine do not show significant age-related changes, consequently the pediatric posology has been extrapolated from the recommended adult dose.
Since renal elimination affects only a small amount of the drug, no pharmacokinetic studies have been performed in patients with kidney failure. Mefloquine and the major metabolite are not appreciably eliminated by hemodialysis, therefore it is not necessary to modify the dose indicated for chemoprophylaxis to obtain plasma concentrations similar to those found in healthy subjects in dialysis patients.
There pregnancy does not significantly modify the pharmacokinetics of mefloquine.
The absorption of mefloquine may be impaired in acute malaria.
Pharmacokinetic differences have been observed between populations of various ethnicities. In practice, however, these are of minor importance compared with the immune status of the host and the sensitivity of the parasite.
During prolonged prophylaxis the elimination half-life of mefloquine remains unchanged.
05.3 Preclinical safety data -
A teratogenic effect was observed after administration of high doses of mefloquine in mice and rats and an embryotoxic effect was seen in rabbits after administration of mefloquine doses 5-20 times higher than those used for therapeutic purposes in humans, but clinical studies did not reveal teratogenic or embryotoxic effects.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Microcrystalline cellulose, lactose, crospovidone, corn starch, ammonium-calcium alginate, poloxamer, talc, magnesium stearate.
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package -
Blisters made of thermoformed plastic material coupled with aluminum tape on both sides, enclosed in a cardboard box together with the package leaflet.
Carton containing 8 tablets of 250 mg
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Roche S.p.A. - Viale G.B. Stucchi, 110 - 20900 Monza (MB)
08.0 MARKETING AUTHORIZATION NUMBER -
"250 mg tablets" 8 tablets AIC n ° 027250024
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: June 1992
Renewal of the authorization: June 2010
10.0 DATE OF REVISION OF THE TEXT -
October 2016
