Nimartem Artemether Lumefantrine Tablets Capsules and Oral Suspension

NimARTEM®

Blood Schizonticide

Artemether/Lumefantrine Antimalarial combination

 

Presentations

TABLETS: Two blisters of 12 Round tablets each

Each tablet contains 20mg Artemether & 120mg Lumefantrine.

CAPSULES: One blister of 12 capsules.

Each capsule contains 40m Artemether & 240mg Lumefantrine.

ORAL SUSPENSION: Powder for Reconstitution containing 180mg Artemether and

1080mg Lumefantnne in a 60ml Opaque plastic bottle.

Each 5ml Teaspoon contains 15mg Artemether and 90mg Lumefantrine.

 

Clinical Pharmacology

Pharmacodynamics

NimARTEM is a fixed combination in a ratio of 1:6.

The food vacuole in the cell of the malarial parasite has been identified to be the site of antiparasitic action of both components, where they are thought to interfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to the non-toxic Hemozoin, which is the malaria pigment Lumefantrine is thought to interfere with the polymerization process, while Artemether generates reactive metabolites as a result of the interaction between its peroxide bridge and the iron component of the Haemglobin. Both Artemether and Lumefantrine have a secondary action involving inhibition of nucleic acid and protein synthesis within the cell of the malarial parasite.

The Antimalarial activity of the combination of Lumefantrine and Artemether is greater than that of either substance alone. The fixed combination of Lumefantrine and Artemether achieves its Antimalarial effect through the sequential large initial reduction in parasite biomass by Artemether and the subsequent removal of all the remaining viable parasites by the intrinsically less active but more slowly eliminated Lumefantrine in a synergistic pattern.

The combination also provides mutual protection of the two antimalarial drugs from the development of resistance, as parasites are never exposed to Artemether alone and relatively few are exposed to Lumefantrine, unprotected by the Artemisinin derivative.

 

Pharmacokinetics

Absorption

Artemether is absorbed fairly rapidly with peak plasma concentrations attained approximately 2 hours after dosing. Absorption of Lumeantrine starts after a lag- time of up to 2 hours and plasma concentration peaks at about 6-8 hours after dosing. This is because Lumefantrine is highly Lipophilic and its absorption is especially enhanced by food, especially fatty foods. Patients are advised to take the medication with a normal diet as soon as food can be tolerated.

 

Distribution

Both Artemether and Lumefantrine are highly bound to human Serum Proteins in vitro (95.4% and 99.9% respectivey) Dihydroartemisinin the most active form of Artemisinin and its derivatives, is also bound to human serum proteins (47- 76%) . Protein binding to human plasma protein appears to be in a linear pattern.

 

Metabolism

Artemether is metabolized in a rapidly and extensive manner (substantial first-pass metabolism) both in humans and in vitro. Microsomes in the human liver metabolize Artemether via Methylaition to the biologically active metabolite Dihydroartemisinin, predominantly through the isoenzyme CYP3A4/5. The pharmacokinetics of this metabolite has also been elucidated in-vivo in humans. The Artemether/ dihydroartemisinin AUC ratio is 1:2 after a single dose and 0:3 after 6 doses given over 3 days.

Lumefantrine is N-debutylated main by CYP3A4 inhuman liver microsomes.

In-vitro, Lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.

 

Elimination

Artemether and dihydroartemisinin are rapidly cleared from plasma with elimination half-life of approximately 2 hours. Lumefantrine is cleared very slowly with a terminal half-life of 2-3 days in healthy volunteers and 4-6 days in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinical relevance to the pharmacokinetics. No urinary excretion data are availabIe for humans.

In rats and dogs, unchanged Artemether has not been detected in faeces and urine due to its rapid and substantial first-pass metabolism, but several unidentified metabolites have been detected in both faeces and urine. Lumefantnne is eliminated via the bile in rats and dogs, with excretion mainly in the faeces. After oral dosing in rats and dogs, qualitative and quantitative recovery of metabolites in the bile and faeces was relatively low, most of the dose being recovered as parent drug.

 

Indications

NimARTEM is a blood Schizonticide indicated for the treatment of acute uncomplicated plasmodium faIciprum malaria or mixed infections including P. falciparum and strains from multidrug resistant areas, in adults and children.

NimARTEM is recommended for use as a stand-by emergency treatment for travelers to areas where resistance to other drugs has been recorded.

 

Contra-Indications

NimARTEM is contra-indicated in:

– Patients with known Hypersensitivity to Artemether, Lumefantrine or to any of the excipients of the drug.

– Patients with severe malaria according to WHO definition.

– First trimester of pregnancy.

– Patients with known electrolyte imbalance disturbance e.g. hypomagnesaemia or hypokalaemia.

– Patients on drugs that are known to prolong the QTC interval such as Antiarrhythmic of classes A1 and III, Neuleptics, antidepressants, etc.

– Patients taking any drug which is metabolized by the cytochrome enzyme CYP2D6 (e.g. Metaoprolol, Flecainide, Imipramine, Amitriptyline, Clomipramine).

– Patients with complicated malaria.

– Patients on any drug that inhibits cytochrome enzyme CYP3A4 (e.g. erythromycin, ketoconazole, Itraconazole, Cimetidine, HIV protease inhibitors).

– Patients with family history of sudden death or of congenital prolongation of the QTC interval on electrocardiograms or with any clinical condition known to prolong the QTC interval.

– Patients with a history of symptomatic arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure, accompanied by reduced left ventricle ejection fraction.

 

ADVERSE REACTIONS

The following adverse effects/reactions have been reported:

– Headache, dizziness, Abdominal pain, Anorexia, sleep disorder, palpitation, diarrhoea, vomiting, nausea, pruritus, rash, cough, myalgia, arthralgia, fatigue, asthenia.

 

Warning and Precaution

The combination of Artemether and Lumefantrine has not been evaluated and is not indicated for prophylaxis.

The combination is active against blood stages of P. vivax but is not active against hypnozoites. Therefore, sequential treatment with Primaquine may be used to achieve hynozoite eradication.

Artemether-Lumefantrine combination has not been evaluated for the treatment of complicated malaria, including other severe manifestations such as Pulmonary Oedema or renal impairment or failure and cases of cerebral malaria.

Combination should not be administered concurrently with other Antimalarial drugs. Administration to patients with severe cardiac, renal or hepatic problems is to be done with caution.
Patients on the drug are advised not to operate machinery or drive.

 

Drug Interactions

The wide therapeutic index and short duration of administration of Artemether Lumefantrine combination reduce significantly the possibilities of interaction with other drugs, although drug interaction studies with some anti-malarials and a member of the Azole antibiotic group elucidated the following in healthy volunteers:

 

With Anti Malarias

Administration of this combination is contraindicated in patients taking medicines that have the capacity to prolong the QT interval.

Due to the chances that patients to be treated with NimARTEM may have recently been treated with some antimalarials e.g. Mefloquine, Quinine, interactions with these two drugs was studied. Oral administration of Artemether/Lumefantrine combination after Mefloquine did not affect the plasma concentration of the Artemether/ dihydroartemisinin (DHA) ratio or Artemether but significantly (approx 30-40%) reduced plasma levels (max and AUC of Lumefantrine).

This reduction was possibly due to lower absorption of Lumefantrine secondary to a mefloquine-induced decrease in bile production. Hence, patients are advised to make up for this decrease in bioavailability by eating at dosing times. I.V. administration of quinine at the same time as Artemether/Lumefantrine combination did not affect plasma concentration of quinine or Lumefantrine. In this study, plasma concentration of Artemether and Dihydroartemisinin appeared to be reduced. I.V. administration of quinine alone seemed to cause a transient.

QTC interval prolongation and this effect slightly but significantly increased when quinine I.V. was given after administration of Artemether/Lumefantrine combination.

This observation seemed to suggest that the risk of QTC prolongation is increased when I.V. quinine is administered after administration of Artemether/Lumefantrine combination.

 

With the Azole Group

Members of this group, e.g. ketoconazole, are known to be potent CYP3A4 inhibitors. Concurrent administration of oral ketoconazole with the drug in healthy volunteers led to a slight increase (less than 2-fold) in Artemether, Dihydroartemisinin and Lumefantrine exposure. No associated increase in side-effects or alterations in electro cardiographic parameters were recorded with the increased exposure to this antimalarial combination. Hence, no dose adjustment of the drug is recommended when administered with ketoconazole or any other CYP3A4 inhibitor, for the treatment of malaria falciparum in patients.

Both Artemether & Lumefantrine are metabolized by CYP3A4 but do not inhibit the enzyme’s activity at the therapeutic concentrations. However, due to lack of clinical data and unknown effects on safety, co-administration of the combination with drugs that inhibit CYP3A4 is contra-indicated. Since Grapefruit inhibits the metabolism of some drugs through CYP3A4, patients are advised not to drink grape-fruit while on this combination.

 

With Concomitant Non-Antimalarial Treatment

Interaction studies have shown no safety issues that may be attributable to drug interactions, especially with antipyretics, antibiotics and electrolyte fluid replacement processes.

 

With CYP450 Enzymes

At therapeutic concentrations of Artemether in in-vitro studies, no significant interactions with cytochrome P450 enzymes were revealed. Artemisinins though, have some capacity to induce the production of CYP2C19 and probably, also CYP3A4 enzymes. It is possible that the therapeutic effects of drugs that are predominantly metabolized by these enzymes could be altered by this iso-enzyme production.

In-vitro, Lumefantrine was found to inhibit CYP2D6 and this may have key clinical relevance for compounds with low therapeutic indices. Co-administration of the combination with drugs that are metabolized by this iso-enzyme (e.g. tricylic antidepressants, neuropletics) is contra-indicated.

 

Pregnancy and Lactation

Since no adequate data from the use of Artemether & Lumefantrine in pregnancy have been recorded in humans, no evidence of teratogenicity for the combination has also been reported in animals (e.g. Rats). However, these results are inconclusive due to uncertain and monitored exposure. Treatment with this combination in pregnancy should be considered only if the expected benefit to the mother out-weighs the risk to the foetus.

No data are available in human although animal data suggest excretion into breast milk. Artemether-Lumefantrine combination should not be taken during lactation/breast feeding and due to the long elimination half-life of Lumefantrine (4 to 6 days), it is advised that breast-feeding should be resumed only at least a week after the last dose of the combination was taken.

 

Dosage and Administration

Capsules, Tablets and Powder for reconstitution (suspension) for oral administration. For enhanced absorption, NimARTEM should be taken with food. If patient is unable to tolerate food, drug should be administered but systemic exposure may be reduced. In the event of vomiting within one hour of dosing, a repeat dose should be administered.

 

CAPSULES AND TABLETS

Adults and Children ≥ 12years of Age or ≥ 35kg Body Weight

A standard 3 days treatment schedule with a total of 6 dose is recommended as follows:

2 (two) capsules or 4 tablets as a single dose at the time of initial diagnosis, again 2 capsules or 4 tablets after 8-12 hours and then 2 capsules or 4 tablets twice daily (morning and evening) on each of the following two days. Total adult course comprises 12 capsules or 24 tablets, given over a period of 60 hours.

DAY DAY ONE (1) DAY TWO (2) DAY THREE (3)
1ST Dose After 8-12 hours Morning Evening Morning Evening
DOSAGES 2 capsules or 4 Tablets 2 capsules or 4 Tablets 2 capsules or 4 Tablets 2 capsules or 4 Tablets 2 capsules or 4 Tablets 2 capsules or 4 Tablets

 

Children ≥ 12 Years of Age or ≥ 35kg body weight

5 to < 13kg body weight (< 3yrs): (Total course = 6 Round Tablets)

One round tablet at the time of initial diagnosis, again one tablet after 8-12 hours and then one tablet twice daily on each of the following 2 days.

15 to <25kg (3-8yrs): (Total course = 12 Round Tablets)

Two Round tablets at the time of initial diagnosis, again two tablets after 8-12 hours and then 2 tablets twice daily on each of the following 2 days.

25 to <35kg (9-14yrs): (Total course = 18 Round Tablets)

Three round tablets at the time initial diagnosis, again 3 tablets after 8-12 hours and then 3 tablets twice daily on each of the following 2 days.

DAYS
DAY 1 DAY 2 DAY 3
BODY WEIGHT AGE 1 DOSE AFTER
8-12 HOURS
MORNING EVENING MORNING EVENING
5 to < 15kg(<3yrs) o o o o o o
5 to < 25kg (3-8yrs) oo oo oo oo oo oo
25 to < 35kg (9-14yrs) ooo ooo ooo ooo ooo ooo
35kg (>14yrs/Adult) oooo oooo oooo oooo oooo oooo

 

POWDER FOR RECONSTITUTION (Oral Suspension)

The Oral suspension contains 180mg Artemetherand 1080mg Lumefantrine in a 60ml Opaque plastic bottle. It is targeted at children aged 0-5 years old and dosage is as follows:

  Dose Regime
BODY WEIGHT DAY 1 DAY 2 DAY 3
5kg 5ml b.i.d 5ml b.i.d 5ml b.i.d
7.5kg 10ml b.i.d 10ml b.i.d 10ml b.i.d
10kg 15ml b.i.d 15ml b.i.d 15ml b.i.d
15kg 20ml b.i.d 20ml b.i.d 20ml b.i.d

 

Symptoms and Treatment of Overdosage

In event of suspected over dosage, symptomatic and supportive therapy should be administered as deemed appropriate, and should include ECG and blood potassium monitoring.

 

Storage

Store below 30°C and protect from heat or direct sunlight. Not to be used after expiry date.

Keep all medicines out of the sight and reach of children.

®Trademark

 

Manufactured by

NEIMETH INTERNATIONAL PHARMACEUTICALS PLC.,

Plot 16, Akanni Doherty Layout,

Oregun, Lagos, Nigeria.

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