PACKAGE LEAFLET: INFORMATION FOR THE USER
Tablet 20/120 mg (CARTEF)
Each uncoated tablet contains:
Artemether ............................................... 20 mg
Lumefantrine USP ................................... 120 mg
Excipients ................................................ q.s.
Composition of excipients:
Microcrystalline Cellulose Powder BP
Hydroxypropyl Methyl Cellulose BP
Polysorbate 80 BP
Maize Starch BP
Purified Water BP
Purified Talc BP
Magnesium Stearate BP
Crospovidone BP
Colloidal Anhydrous Silica BP
Tablet 40/240 mg (CARTEF 40/240)
Each uncoated tablet contains:
Artemether ............................................... 40 mg
Lumefantrine .......................................... 240 mg
Excipients ................................................ q.s.
Composition of excipients:
Microcrystalline Cellulose Powder BP
Hydroxypropyl Methyl Cellulose BP
Polysorbate 80 BP
Maize Starch BP
Purified Water BP
Purified Talc BP
Magnesium Stearate BP
Crospovidone BP
Colloidal Anhydrous Silica BP
Tablet 80/480 mg (CARTEF-DS)
Each uncoated tablet contains:
Artemether ............................................... 80 mg
Lumefantrine USP ................................... 480 mg
Excipients ................................................ q.s.
Description
Artemether + Lumefantrine Tablets, a fixed-dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent.
Artemether + Lumefantrine Tablets contain artemether and lumefantrine, which are blood schizontocides.
Artemether is a synthetic antimalarial derived from artemisinin. Its mechanism of action involves an interaction with ferriprotoporphyrin IX ("heme"), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a haemoglobin degradation by-product derived from proteolysis of haemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen- and carbon-centered radicals.
Lumefantrine is a dichlorobenzylidine derivative given by mouth in combination with artemether for the treatment of uncomplicated falciparum malaria. It is a blood schizontocide with a relatively slow onset of action, but it has a longer duration of action. Lumefantrine is given over a period of 60 hours in combination with artemether, administered at diagnosis. Treatment with artemisinin and its derivatives appears to be generally well tolerated, although there have been reports of mild gastrointestinal disturbance, dizziness, tinnitus, neutropenia, elevated liver enzyme values, and ECG abnormalities, including prolongation of the QT interval.
Indications
Severe falciparum malaria, cerebral malaria, multi-drug resistant malaria.
It is indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria in adults, children and infants of 5 kg and above.
Consideration should be given to official guidance regarding the appropriate use of antimalarial agents.
Limitations of Use
Artemether + Lumefantrine Tablets/Suspension are not approved for patients with severe or complicated P. falciparum malaria.
Artemether + Lumefantrine Tablets/Suspension are not approved for the prevention of malaria.
Contraindications
Artemether + Lumefantrine Tablets are contraindicated in:
Patients with severe malaria.
Patients who are taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (e.g. flecainide, metoprolol, imipramine, amitriptyline, clomipramine).
Patients with a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.
Patients taking drugs that are known to prolong the QTc interval. These drugs include:
Antiarrhythmics of Classes IA and III.
Neuroleptics and antidepressant agents.
Certain antibiotics including some agents of the following classes:
Macrolides
Fluoroquinolones
Imidazole and triazole antifungal agents
Certain non-sedating antihistamines (terfenadine, astemizole)
Cisapride
Patients with a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricular ejection fraction.
Special Precautions
Artemether + Lumefantrine Tablets must not be used in the first trimester of pregnancy in situations where other suitable and effective antimalarials are available.
Artemether + Lumefantrine Tablets should not be given concurrently with any other antimalarial agent unless there is no other treatment option.
If quinine is given after Artemether + Lumefantrine Tablets, close monitoring of the ECG is advised.
If Artemether + Lumefantrine Tablets are given after mefloquine, close monitoring of food intake is advised.
Artemether + Lumefantrine Tablets are not indicated for the treatment of malaria due to P. vivax, P. malariae or P. ovale, although some patients in clinical studies had co-infection with P. falciparum and P. vivax at baseline.
Artemether + Lumefantrine Tablets are active against blood stages of Plasmodium vivax, but are not active against hypnozoites.
Artemether + Lumefantrine Tablets are not indicated and have not been evaluated for prophylaxis.
Caution is advised when administering Artemether + Lumefantrine Tablets to patients with severe renal, hepatic or cardiac problems.
Avoid concomitant use of drugs known to prolong the QT interval or monitor such patients.
Renal/hepatic disease: Avoid combination with Pyrimethamine/Sulfadoxine.
Paediatric: Reduce the dose according to weight.
Pregnancy: Avoid, especially in the 1st trimester.
Lactation: Use with caution.
Elderly: Reduce the dose according to body weight.
Side Effects
The most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache.
Drug Interactions
Rifampin
Oral administration of rifampin, a strong CYP3A4 inducer, with Artemether + Lumefantrine Tablets/Suspension resulted in a significant decrease in exposure to artemether, dihydroartemisinin (DHA, the metabolite of artemether), and lumefantrine by 89%, 85% and 68%, respectively, when compared to exposure values after Artemether + Lumefantrine Tablets/Suspension alone.
Concomitant use of strong inducers of CYP3A4, such as rifampin, carbamazepine, phenytoin and St. John's wort, is contraindicated with Artemether + Lumefantrine Tablets/Suspension.
Ketoconazole
Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Artemether + Lumefantrine Tablets/Suspension resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine in a study of 15 healthy subjects.
No dose adjustment of Artemether + Lumefantrine Tablets/Suspension is necessary when administered with ketoconazole or other potent CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine, which could lead to QT prolongation, Artemether + Lumefantrine Tablets/Suspension should be used cautiously with drugs that inhibit CYP3A4.
Antiretroviral Drugs
Both artemether and lumefantrine are metabolized by CYP3A4.
Antiretroviral drugs, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4.
Therefore, the effects of antiretroviral drugs on the exposure to artemether, DHA, and lumefantrine are also variable.
Artemether + Lumefantrine Tablets/Suspension should be used cautiously in patients on antiretroviral drugs because decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Artemether + Lumefantrine Tablets/Suspension, and increased lumefantrine concentrations may cause QT prolongation.
Prior Use of Mefloquine
Administration of three doses of mefloquine followed 12 hours later by a 6-dose regimen of Cartef Tablets in 14 healthy volunteers demonstrated no effect of mefloquine on plasma concentrations of artemether or the artemether/DHA ratio.
However, exposure to lumefantrine was reduced, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production.
Patients should be monitored for decreased efficacy, and food consumption should be encouraged with administration of Artemether + Lumefantrine Tablets/Suspension.
Hormonal Contraceptives
In vitro, the metabolism of ethinyl estradiol and levonorgestrel was not induced by artemether, DHA, or lumefantrine.
However, artemether has been reported to weakly induce, in humans, the activity of CYP2C19, CYP2B6, and CYP3A.
Therefore, Cartef Tablets may potentially reduce the effectiveness of hormonal contraceptives.
Patients using oral contraceptives, transdermal patches, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control.
CYP2D6 Substrates
Lumefantrine inhibits CYP2D6 in vitro.
Administration of Artemether + Lumefantrine Tablets/Suspension with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects.
Many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Cartef Tablets due to the potential additive effect on the QT interval (e.g. flecainide, imipramine, amitriptyline, clomipramine).
Sequential Use of Quinine
A single dose of intravenous quinine (10 mg/kg body weight), concurrent with the final dose of a 6-dose regimen of Artemether + Lumefantrine Tablets/Suspension, demonstrated no effect of intravenous quinine on the systemic exposure of DHA or lumefantrine.
Quinine exposure was also not altered.
Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant.
However, quinine and other drugs that prolong the QT interval should be used cautiously following treatment with Cartef Tablets due to the long elimination half-life of lumefantrine and the potential for additive QT effects. ECG monitoring is advised if use of drugs that prolong the QT interval is medically required.
Interaction with Drugs that are Known to Prolong the QT Interval
Artemether + Lumefantrine Tablets/Suspension is to be used with caution when co-administered with drugs that may cause prolonged QT interval, such as:
Antiarrhythmics of Classes IA and III
Neuroleptics
Antidepressant agents
Certain antibiotics, including some agents of the following classes:
Macrolides
Fluoroquinolones
Imidazole antifungals
Triazole antifungals
Adverse Effects
Like all medicines, Artemether + Lumefantrine Tablets can cause side effects, although not everybody gets them.
Most of the side effects are mild to moderate and generally disappear after a few days to a few weeks after treatment.
Some side effects are more commonly reported in children and others are more commonly reported in adults. In cases where there is a difference, the frequency listed below is the more common one.
Some side effects could be serious and need immediate medical attention.
Rare (affecting less than 1 in 1,000 patients)
If you get a rash, swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing, tell your doctor straight away. These are signs of an allergic reaction.
Possible side effects or secondary effects
Very common (affecting more than 1 in 10 patients)
Fast heartbeat
Headache
Dizziness
Cough
Being sick (vomiting)
Stomach pain
Feeling sick (nausea)
Joint or muscle aches
Loss of appetite
General weakness
Tiredness
Trouble with sleeping
Common (affecting less than 1 in 10 patients)
Heart rhythm disturbances (called QTc prolongation)
Symptoms such as unexplained persistent nausea, stomach problems, loss of appetite or unusual tiredness or weakness (signs of liver problems)
Diarrhoea
Abnormal walking
Tingling or numbness of the hands and feet
Rash or itching of the skin
Insomnia
Uncommon (affecting less than 1 in 100 patients)
Inability to coordinate movements
Muscle twitching
Decreased skin sensitivity
Sleepiness
These side effects have been reported in adults and adolescents above 12 years of age.
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.
Pregnancy and Lactation
Pregnancy
Artemether + Lumefantrine Tablets are suspected to cause serious birth defects when administered during the first trimester of pregnancy. Therefore, they must not be used during the first 3 months of pregnancy if it is possible to use an alternative medicine first.
However, they should not be withheld in life-threatening situations where no other effective antimalarials are available.
During the second and third trimesters, treatment should only be considered if the expected benefit to the mother outweighs the risk to the foetus.
Lactation
Women taking Artemether + Lumefantrine Tablets should not breast-feed during treatment.
Due to the long elimination half-life of lumefantrine (4 to 6 days), it is recommended that breast-feeding should not resume until at least one week after the last dose of Artemether + Lumefantrine Tablets, unless the potential benefits to the mother and child outweigh the risks of Artemether + Lumefantrine Tablets treatment.
Precautions for Drug Administration
Artemether + Lumefantrine Tablets/Suspension should be taken with food or drinks rich in fat, such as milk.
Please ask your doctor for advice on the best food or drinks to take Artemether + Lumefantrine Tablets/Suspension with.
If any dose is missed
Try to make sure that you do not miss any doses.
However, if you do forget a dose of Artemether + Lumefantrine Tablets, take the missed dose as soon as you remember unless it is almost time for your next dose.
Then take your next dose at the usual time.
Ask your doctor for advice.
Do not take a double dose to make up for a forgotten dose.
Discontinuation of Treatment
For the treatment of children and infants, the 24-tablet pack should be prescribed.
The prescriber and pharmacist should instruct the parent or caregiver on the posology for their child and that a variable number of tablets (depending on the child's body weight) will be required for the full treatment.
Therefore, the whole pack may not be used.
Discontinuation of Treatment
After successful treatment, the remaining tablets should be discarded or returned to the pharmacist.
Overdosage
In cases of suspected overdosage, symptomatic and supportive therapy should be given as appropriate, which should include ECG and blood potassium monitoring.
Effects on the Ability to Drive and Operate Machinery
Patients receiving Artemether + Lumefantrine Tablets/Suspension should be warned that dizziness or fatigue/asthenia may occur, in which case they should not drive or use machines.
MADE IN INDIA
Storage
Store in a dry place below 30°C.
Keep the medicine out of the reach of children.
Validity Term
36 months
Presentation
Artemether + Lumefantrine:
20 + 120 mg Tablets in a blister pack.
40 + 240 mg Tablets in a blister pack.
80 + 480 mg Tablets in a blister pack.
Marketed by
GB PHARMA LIMITED
65 Chatsworth Road,
London NW2 4BG,
United Kingdom
Tel.: +44 (0) 20 8830 1057
Fax: +44 (0) 20 8830 4807
E-mail: info@gbpharma.co.uk