Artelife α-β Arteether Injection

Artelife

α-β Arteether Injection

 

COMPOSITION

Each 2ml contains

α-β Arteether 150mg

Arachis Oil q.s.

 

PHARMACOLIGAL CLASSIFICATION

Anti-malarial.

 

INDICATION

It is indicated for the treatment of complicated and uncomplicated P. falciparum malaria, including cerebral malaria. It is available as injection for intramuscular use only.

It is indicated as second-line treatment of Chloroquine resistant malaria.

 

DESCRIPTION

α-β Arteether is an efficient erythrocytic schizontocidal drug. α-β Arteether is an oil-soluble ethyl ether derivative of dihydroartemisinin, which shows rapid schizonticidal action and brings about quick clinical improvement in falciparum malaria with low recrudescence rate. It has some gametocidal action too, which aids in cutting down the transmission of falciparum malaria.

 

PHARMACODYNAMICS

α-β Arteether acts at the erythrocytic stage of malarial parasite. It is proposed that the intra-parasitic haem reduces the endoperoxide bridge (the functional group responsible for antimalarial activity of α-β Arteether), releasing a highly reactive free radical iron (IV) oxo species, which alkalytes and oxidises proteins and lipids causing lysis of the parasitic cell. The membrane of the parasite is damaged by lipid peroxidation and channel proteins’ inactivation. It is also proposed that α-β Arteether may also inactivate ribosomes and inhibit protein synthesis. Parasitic clearance times of α-β Arteether are shorter than those with chloroquine and also the response is symptomatic.

 

PHARMACOKINETICS

• Route of administration: α-β Arteether is rapidly absorbed when administered intramuscularly.

• Metabolism: It is metabolized in the liver to the de-ethylated derivative dihydroartemisinin.

• Half-life: >20 hours.

• Elimination: Metabolized by the liver, it is eliminated slowly as compared to other artemisinin derivatives.

 

DOSAGE AND ADMINISTRATION

α-β arteether is for intramuscular use only.

Adult – 150mg i.e. 1 ampoule of α-β arteether once daily for 3 consecutive days.

The injection must be administered under aseptic conditions as deep intramuscular injection in the upper-lateral quadrant of the buttock.

No other drug should be mixed in the same syringe.

 

CONTRAINDICATIONS

α-β Arteether is contraindicated in patients showing hypersensitivity to artemisinin derivatives.

 

USE IN PREGNANCY

Safety of α-β Arteether during pregnancy is not established. However, in case of severe infection with P. falciparum in a pregnant woman, if the potential benefit to the patient justifies the potential risk to the fetus, it may be used with caution in these women.

 

USE IN LACTATION

It is not known whether α-β Arteether is secreted in human milk. As most of the drugs are, lactating women on α-β Arteether therapy should not breast-feed their infants.

 

WARNINGS AND PRECAUTIONS

During the treatment of cerebral malaria and complicated malaria, general supporting therapy should be carried out.

 

ADVERSE REACTIONS

• Adverse effects such as nausea, dizziness, tinnitus, depressed GI tract activity, neutropenia, ECG abnormalities including prolongation of QT interval may occur.

• α-β Arteether is generally well tolerated without any significant clinical, neurological and biochemical toxicity. Neurotoxicity (at high doses, seen in animals) is manifested as gait disturbances, loss of spinal cord pain responses, incoordination, respiratory depression, convulsions and cardio respiratory arrest.

• Apart from some increase in eosinophil count, no other haematological abnormality has been reported.

 

DRUG INTERACTIONS

Quinine and halofantrine are known to prolong the QT interval when used along with α-β Arteether.

Caution should be exercised while using these drugs.

 

OVERDOSAGE

There is no experience with overdosage of α-β Arteether.

 

STORAGE INSTRUCTIONS

Store below 25oC. Protect from light.

 

PRESENTATION AND PACKING

3 x 2 ml amber coloured ampoule.

 

NAFDAC Reg. No. B4-4774

 

Manufactured In India by

Ciron Drugs & Pharmaceuticals Pvt. Ltd.

N-118/119, M.I.D.C., Tarapur,

Boisar, Dist. Thane – 401 506.

http://www.cironpharma.com

 

Manufactured for

CHEZ RESOURCES PHARMA NIG. LTD.

7, Calabar Street,

Onitsha, Anambra State,

Nigeria.

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.

Falcimon Amodiaquine and Artesunate Hydrochloride Tablets SmPC

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Falcimon 100/270 B/L

 

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Falcimon 100/270 B/L is a fixed dose combination of amodiaquine and artesunate.

Each uncoated bilayered tablet contains 100 mg of artesunate and 352.66mg of amodiaquine hydrochloride equivalent to 270 mg of amodiaquine.

Excipients with known effect: each uncoated bilayered tablet contains 360.5 mg of lactose. For the full list of excipients, see section 6.1.

 

3 PHARMACEUTICAL FORM

Tablet.

Capsule shaped, uncoated, bilayered, biconvex tablet with one white to light yellowish layer and the other yellow layer debossed with ‘100’ on one side and with central break-line on the white to light yellowish layer. The break-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

 

4 CLINICAL PARTICULARS

4.1 Therapeutic Indication

Falcimon 100/270 B/L is indicated for the treatment of uncomplicated cases of malaria due to Plasmodium falciparum strains which are susceptible to amodiaquine as well as to artesunate.

The most recent official guidelines on the appropriate use of antimalarial agents and local information on the prevalence of resistance to antimalarial drugs must be taken into consideration for deciding on the appropriateness of therapy with Falcimon 100/270 B/L.

Official guidance will normally include WHO (http://whqlibdoc.who.int/publications/2010.odf) and public health authorities guidelines (see also sections 4.4 and 5.1).

Falcimon 100/270 B/L should not be used in regions where amodiaquine resistance is widespread (see also sections 4.4 and 5.2 regarding pharmacokinetic interactions between artesunate and amodiaquine).

 

4.2 Posology and method of administration

Oral use

The dosage of artesunate and amodiaquine is:

– 4 mg/kg (range 2 to 10 mg/kg) body weight of artesunate and

– 10 mg/kg (range 7.5 to 15 mg/kg) body weight of amodiaquine base once daily for 3 days.

Weight range
(approximate age range)
1st day of treatment 2nd day of treatment 3rd day of treatment
≥ 4.5kg to <9 kg (2 to 11 months)* 25 mg AS
67.5 mg AQ
25 mg AS
67.5 mg AQ
25mg AS
67.5 mg AQ
≥ 9kg to <18kg (1 to 5 years)* 50 mg AS

135 mg AQ

50 mg AS

135 mg AQ

50 mg AS

135 mg AQ

≥ 18kg to <36kg (6 to 13 years)* 100 mg AS
270mg AQ
100 mg AS
270mg AQ
100 mg AS
270mg AQ
≥ 36kg (14 years and above)* 200 mg AS
540 mg AQ
200 mg AS
540 mg AQ
200 mg AS
540 mg AQ

* If a weight-age mismatch occurs, dosing should be weight-based.

AS: artesunate

AQ: amodiaquine

Falcimon 100/270 B/L should not be taken with a high-fat meal (see section 5.2). The tablets should be swallowed with water.

For very young children or patients not able to swallow the tablets whole, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately.

Should vomiting occur within half an hour after dosing, a repeated dose of Falcimon 100/270 B/L is to be taken. In case of further vomiting, treatment for severe malaria should be considered.

 

Renal/hepatic impairment

No data are available on dosing in hepatically or renally impaired patients (see section 4.4).

 

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

• History of liver injury during treatment with amodiaquine.

• Previous haematological event during treatment with amodiaquine.

• Retinopathy (in case of frequent treatment).

Falcimon 100/270 B/L must not be used for malaria prophylaxis, since it may result in agranulocytosis and severe hepatotoxicity (see section 4.4).

 

4.4 Special warnings and precautions for use

Falcimon 100/270 B/L should not be used in regions where amodiaquine resistance is widespread, as the treatment with the combination under such conditions may mean effectively a treatment with artesunate alone with an insufficient duration and decreased plasma concentrations as compared to artesunate alone (see section 4.5). As a result, the risk of development of resistance of P. falciparum to artesunate increases significantly.

Amodiaquine is effective against some chloroquine-resistant strains of P. falciparum, although there is cross- resistance.

Falcimon 100/270 B/L has not been evaluated for the treatment of complicated malaria and is therefore not recommended.

Falcimon 100/270 B/L has not been evaluated in the treatment of malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale and is therefore not recommended.

Falcimon 100/270 B/L has not been evaluated for malaria prophylaxis. The use of amodiaquine for prophylaxis results in an unacceptably high risk of agranulocytosis and liver toxicity and is contraindicated. Therefore, the combination of amodiaquine and artesunate is also contraindicated for malaria prophylaxis (see section 4.3). It is not known, whether the toxicity of amodiaquine, observed with prophylactic use (i.e. agranulocytosis, hepatotoxicity), may also develop after repeated cycles of curative treatment.

Falcimon 100/270 B/L has not been studied specifically in patients with thalassaemia, sickle cell anaemia or G6PD deficiency.

In the absence of specific clinical studies, caution should be exercised in patients with renal or hepatic impairment.

Symptoms suggestive of the following diseases should be carefully monitored:

• Hepatitis, pre-icteric phase and especially when jaundice has developed.

• Agranulocytosis (as suggested, for instance, by a clinical condition including fever and/or tonsillitis and/or mouth ulcers).

When these symptoms develop or exacerbate during the course of therapy with Falcimon 100/270 B/L, laboratory tests for liver function and/or blood cell counts should be performed at once. Immediate discontinuation of treatment may be required.

In such cases, continuation of treatment with amodiaquine increases the risk of death.

Cardiovascular effects have been reported with other amino-4-quinoline derivatives during high dose treatment. There is no evidence that an overdose of amodiaquine causes any of the life-threatening cardiovascular complications often seen after an overdose of chloroquine. However, by chemical class analogy, caution should be exercised, especially with patients who have recently taken other antimalarial drug with cardiovascular side effects (quinine, quinidine, halofantrine, lumefantrine, mefloquine) or those who are under treatment with cardiovascular drugs or other drugs with the potential to prolong the QT interval (see section 4.9 overdosage).

The combination of artesunate and amodiaquine may induce neutropenia (see section 4.8) and increase the risk of infection.

Acute extrapyramidal disorders may occur with Falcimon 100/270 B/L, even after administration of a single dose (see section 4.8). These adverse reactions usually resolve after treatment discontinuation of Falcimon 100/270 B/L and appropriate medical treatment of the neurological condition. Alternative antimalarial therapy should be instituted.

Caution is advised when combining Falcimon 100/270 B/L with drugs inhibiting, inducing or competing for CYP2C8 (see section 4.5).

Co-administration of Falcimon 100/270 B/L and efavirenz should be avoided, since this combination has been noted to cause marked hepatotoxicity.

Excipients

Falcimon 100/270 B/L contains a small amount of lactose. Patients with rare hereditary oroblems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption may experience symptoms of intolerance.

 

4.5 Interactions with other medicinal products and other forms of interaction

Interactions with drugs used for treatment of HIV and/or tuberculosis may occur, though little clinical data is available. Prescribers should be vigilant for adverse events potentially related to such interactions, including liver toxicity and neutropenia.

In the absence of clinical data, Falcimon 100/270 B/L is not recommended to be administered concomitantly with drugs known to inhibit the liver enzymes cytochrome (CYP) 2A6 (e.g. methoxsalen, pilocarpine, tranylcypromine) and/or CYP2C8 (e.g. trimethoprim, ketoconazole, ritonavir, saquinavir, lopinavir, gemfibrozil, montelukast,) (see section 5.2).

No pharmacokinetic interactions of artesunate with other antimalarial drugs of importance have been identified. However, concomitant administration of Falcimon 100/270 B/L with other antimalarial treatments is not recommended, as no data on efficacy and safety are available.

A statistically significant decrease in dihydroartemisinin (DHA), the main active metabolite of artesunate, occurs with concomitant use of artesunate and amodiaquine (Cmax decreased 47%, AUC0-inf decreased 17%).

Agranulocytosis and hepatitis have been reported following the use of amodiaquine in long term prophylaxis treatments (see section.4.8). Therefore, caution should be observed when prescribing amodiaquine containing products, such as Falcimon 100/270 B/L, concurrently with other drugs with a potential for liver and/or haematological toxicity.

Though no pharmacokinetic interactions have been documented, amodiaquine and desethylamodiaquine inhibit CYP 2D6 in vitro and may cause clinically significant interactions with some β-blockers, antidepressants, and antipsychotic drugs. Caution should be exercised when co-administration of these agents with Falcimon 100/270 B/L is deemed necessary.

 

4.6 Fertility, pregnancy and lactation

Pregnancy

Malaria is known to be particularly hazardous during pregnancy. The benefits and risks of therapy with Falcimon 100/270 B/L to mother and foetus must be assessed by the prescriber.

The safety of amodiaquine in pregnant women has not been conclusively established, although many years of experience with the drug have not indicated any teratogenicity.

Data on a limited number of exposed pregnant women do not indicate any adverse effect of artemisinins on pregnancy or on the health of the foetus/newborn child. Animal data indicate a limited embryotoxic effect at doses of 6 mg/kg/day or more (see section 5.3).

During 1st trimester of pregnancy, Falcimon 100/270 B/L should not be used unless clearly necessary e.g. if treatment is life-saving for the mother, and if another antimalarial is not suitable or not tolerated. During 2nd or 3rd trimesters of pregnancy, Falcimon 100/270 B/L may be used with caution, only if other antimalarials are unsuitable.

 

Breast feeding

The amounts of antimalarials in breast milk are small. Therefore, lactating women can receive artemisinin based combination therapies (including Falcimon 100/270 B/L) for malaria treatment.

 

Fertility

No specific studies with Falcimon 100/270 B/L in humans have been conducted to evaluate effects on fertility. Studies in animals showed effects on fertility (see section 5.3). The significance for human is unknown. 4.7 Effects on the ability to drive and use machines.

Patients receiving Falcimon 100/270 B/L should be warned that somnolence, dizziness or asthenia may occur, in which case they should not drive or use machines.

 

4.8 Undesirable effects

The tolerability to the fixed combination amodiaquine and artesunate has been evaluated through two studies involving 1003 patients treated with the fixed dose combination: one conducted in Burkina- Faso, and another one conducted in Senegal, Cameroon, Mali, and Madagascar. The tolerability was evaluated as comparable to reference treatments.

About 30% of treated patients experienced adverse reactions. Most of the reported adverse reactions were similar to symptoms usually seen during a malaria attack.

The most frequent adverse reactions observed were: anorexia, abdominal pain, nausea, asthenia, somnolence, insomnia and cough (see hereafter). The most serious adverse reactions observed were: asthenia, anaemia and vertigo.

The adverse events considered at least possibly related to the treatment (adverse reactions) are listed hereafter by body system, organ class and absolute frequency.

The adverse reactions are ranked under body-system and frequency using the following convention: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥1/10,000 to <1/1000; very rare: < 1/10,000; not known: cannot be estimated from the available data.

The type and frequencies of all adverse reactions observed from the two pivotal studies are summarised hereafter:

Class-organ Frequency Adverse reactions
Infections and infestations Uncommon Bronchitis acute, gastroenteritis, oral candidiasis
Blood and lymphatic system disorders Uncommon Anaemia
Metabolism and nutrition disorders Uncommon Hypoglycaemia
Psychiatric disorders Common

Uncommon

Anorexia, insomnia

Hallucination

Nervous system disorders Common

Uncommon

Somnolence

Paraesthesia

Eye disorders Uncommon Ocular icterus
Ear and labyrinth disorders Uncommon Vertigo
Cardiac disorders Uncommon Arrhythmia, bradycardia
Respiratory, thoracic, and mediastinal disorders Common Cough
Gastro-intestinal disorders Common

Uncommon

Nausea, abdominal pain

Diarrhoea, vomiting

Skin and subcutaneous tissue disorders Uncommon Pruritus, rash, face oedema, skin disorders
Musculoskeletal and
connective tissue disorders
Uncommon Arthralgia
General disorders and
administration site conditions
Common

Uncommon

Asthenia

Oedema peripheral, pyrexia

 

Post-marketing experience

Frequency not known: Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) have been reported. These adverse reactions usually resolved after discontinuation of Falcimon 100/270 B/L and appropriate medical treatment (see section 4.4).

In published literature data, generated mostly during post-approval use of amodiaquine and/or artesunate, additional types of events have been reported. Since frequency estimates are highly variable across the studies, no frequencies are given for these events. For some of these events, it is unclear whether they are related to amodiaquine/artesunate or occur as a result of the underlying disease process:

– Headache, dizziness

– Cold, flu, rhinitis, shivering, sore throat

– Convulsion

– Splenomegaly, jaundice

– Allergic reaction

 

The following adverse reactions have been reported with amodiaquine, especially at higher doses and/or during prolonged treatment; their frequency is not known:

• Blood and lymphatic system disorders: cases of leucopenia and neutropenia (agranulocytosis)

• Nervous system disorders: rare neuromyopathy

• Eye disorders, varying in type and severity: transient accommodation disorders, corneal opacifications regressive once treatment is Stopped, very rarely, irreversible retinopathy justifying specialist ophthalmic attention.

• Hepato-biliary disorders: severe and sometimes fatal hepatitis.

• Skin and subcutaneous disorders: slate-grey pigmentation, notably affecting the fingers and mucou membranes.

If any of the side effects is serious or unexpected, you should inform the supplier (see section 7) and/or health authority, as per local regulation.

 

4.9 Overdose

In cases of suspected overdose, the patient should be urgently transferred to a specialized unit when appropriate monitoring and symptomatic and supportive therapy should be applied.

 

Amodiaquine

• The dangerous dose of amodiaquine cannot be stated precisely because of the low number of known cases; by analogy with chloroquine, it can be estimated at around 2 grams as a single administration ii adults.

• Symptoms: headache, dizziness, visual disorders, cardiovascular collapse and convulsions, followed by early respiratory and cardiac arrest. Cases of extrapyramidal disorders have been reported.

 

Artesunate

No cases of overdose have been reported to date.

 

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Artemisinin and derivatives, combinations; ATC code: P01BF03 Falcimon 100/270 B/L is an artemisinin-based combination therapy which consists of two blood schizonticide with independent modes of action and different intraparasitic biochemical targets.

Falcimon 100/270 B/L is indicated in areas where parasite resistance rate to amodiaquine remains below the threshold defined by WHO.

Efficacy and safety of amodiaquine + artesunate in uncomplicated P falciparum malaria have been demonstrated in clinical trials in West and Central Africa and in Madagascar.

Inconsistent results have been seen in some areas where combinations of artesunate and amodiaquine have been studied, probably due to a higher prevalence of amodiaquine resistance.

 

Artesunate: Artesunate is a hemisuccinate derivative of dihydroartemisinin, which is obtained by the reductiol of artemisinin, a sesquiterpene lactone endoperoxide extracted from a plant used in traditional Chinese medicine, known as sweet or annual wormwood (Artemisia annua).

The chemical mechanism of action of artesunate has been widely studied and appears well established. The artesunate endoperoxide bridge is split by haeme within the infected erythrocyte, generating singlet oxygen. Parasite proteins, particularly in membranous structures, are thus alkylated, leading to parasite death. In-vitro experiments in P falciparum have shown that artemisinin derivatives are active against a broad spectrum of the life cycle of the parasite, from the relatively inactive ring stage to late schizonts. The schizonticidal and gametocytocidal activities of artesunate, administered orally have been demonstrated in vivo on chloroquine-sensitive strains of Plasmodium (P. berghei in mice and P. knowlesi in monkeys) and on chloroquine-resistant strains (P. berghei in mice).

In-vitro, artesunate appears to be inactive against extra-erythrocyte forms, sporozoites, liver schizontes merozoites.

When administered orally, artesunate consistently acts more quickly than orally administered chloroquine and intravenous quinine in all animal models studied, regardless of the strain or dose tested. In macaques (the animal model most similar to humans) infected with a chloroquine-resistant strain of P. knowlesi, cure was obtained with the same dose of artesunate and quinine.

 

Amodiaquine: Amodiaquine is a synthetic 4-aminoquinoline antimalarial. Its activity is characterized by schizonticidal action on Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malaria by destroying intraerythrocytic forms.

The mechanism of action of 4-aminoquinoline derivatives against plasmodium is not yet completely know. It is nonetheless accepted that these derivatives, one of which is amodiaquine, penetrate the infected red blood cells and prevent the parasite from polymerizing haeme into an insoluble product called haemozoin, leading to parasite death.

Strains of Plasmodium falciparum resistant to 4-aminoquinolines (chloroquine, amodiaquine) are present many areas, and their geographical distribution is constantly changing. However, amodiaquine remains active against some chloroquine-resistant P. falciparum strains.

 

Pharmacokinetic properties

Artesunate

Absorption

After oral administration, absorption is rapid. Most of the artesunate is promptly biotransformed, mainly through plasma esterases, into the active metabolite dihydroartemisinin (DHA).

A bioequivalence study was conducted with a fixed dose combination product containing 270 mg amodiaquine 100 mg artesunate, which is qualitatively and with respect to the ratio of active and other ingredients essentially the same as Falcimon 100/270 B/L.

After administration of 1 tablets containing amodiaquine and artesunate (270 mg and 100 mg respectively) in healthy volunteers, the mean (± SD) artesunate Cmax value was 185 ng/ml (±131), and the corresponding value for AUC was 114 ng.h/ml (±57). The mean artesunate tmax value was 0.38 hours.

 

Distribution

DHA has been shown to substantially accumulate in P. falciparum-infected erythrocytes.

Artesunate is not significantly protein-bound.

 

Metabolism

Artesunate is extensively hydrolysed by plasma esterases and perhaps also by CYP2A6.

Its main metabolite, is presumed to account for most of the in vivo antimalarial activity.

DHA is further metabolised through glucuronidation prior to excretion.

 

Elimination

Artesunate has a plasma half-life of 3-29 minutes. The active metabolite DHA has a plasma half-life of 40 to 95 minutes. The modes of excretion of DHA have not been fully elucidated.

 

Amodiaquine

Absorption

After oral administration in healthy subjects, amodiaquine is quickly absorbed and biotransforrned into its main active form, desethylamodiaquine. The absolute bioavailability of amodiaquine is not known.

No pharmacokinetic data are available for Falcimon 100/270 B/L. A bioequivalence study was conducted with a fixed dose combination product containing 270 mg amodiaquine and 100 mg artesunate, which is qualitatively and with respect to the ratio of active and other ingredients essentially the same as Falcimon 100/270 B/L.

After administration of 1 tablet containing amodiaquine and artesunate (270 mg and 100 mg respectively) in healthy volunteers, the mean (±SD) amodiaquine Cmax value was 9.3 ng/ml (±4.5), and the corresponding value for AUC was 72 ng.h/ml (±24). The mean amodiaquine tmax value was 0.7 (±26) hours.

 

Distribution

The volume of distribution of amodiaquine is estimated at 20 to 40 l/kg.

Desethylamodiaquine, the main metabolite of amodiaquine, is assumed to be the main active form after oral administration. It is mainly found in blood, at much higher concentrations than unchanged amodiaquine. Its concentration in whole blood is 4-6 times higher than in plasma.

 

Metabolism

The hepatic first pass metabolism of amodiaquine is high, with formation of the active metabolite, ethylamodiaquine, presumably via the CYP2C8 isoenzyme. Further metabolism includes oxidation and glucuronoconjugation.

 

Elimination

Amodiaquine is eliminated principally through biotransformation with only around 2% excreted unchanged in urine. Desethylamodiaquine is slowly eliminated with a terminal half-life of 9-18 days.

 

Artesunate and amodiaquine interaction

Single dose data have shown that the co-administration of artesunate and amodiaquine leads to a 47% decrease in the Cmax of dihydroartimisinin, and a 17% decrease of its AUC0-inf, relative to what is seen when artesunate is administered alone. If Falcimon 100/270 B/L is used in the presence of amodiaquine resistance, this might further compromise the antimalarial activity of Falcimon 25/67.5 B/L (see also sections 4.1, 4.4 and 5.1).

 

Special populations

For the combined use of artesunate and amodiaquine, no pharmacokinetic data are available for patients with impaired renal or hepatic function.

 

Food effect

When fixed combination of amodiaquine/artesunate was taken with a high fat meal in healthy volunteers, the Cmax and AUC(0-t) of amodiaquine increased 23% and 58% respectively, compared to fasting. The Cmax and AUC(0-t) of the active metabolite desethylamodiaquine (DeAQ) increased 18% and 12% respectively with a high-fat meal, compared to fasting.

Conversely, when fixed combination of amodiaquine/artesunate was taken with a high fat meal in healthy volunteers, the Cmax and AUC(0-t) of artesunate decreased 66% and 13% respectively, compared to fasting. The Cmax and AUC(0-t) of the active metabolite dihydroartemisinin (DHA) decreased 48% and 5% respectively with a high-fat meal, compared to fasting.

 

5.3. Preclinical safety data

General toxicity

Artesunate presents low acute toxicity. After repeated administration of 50 mg/kg/day in rats and 82.5 mg/kg/day in dogs, i.e. 5 and 8.25 times the proposed maximal therapeutic dose in man it is potentially toxic to the haematopoietic organs, the immune system and response, the liver and kidneys.

For amodiaquine histopathological changes (pigmentation) were seen in the heart at 30 mg/kg/day in rats. The statistically significant effects seen in vitro on ion channels in the heart at 0.1 µM in the hERG current (expressed in Human Embryonic Kidney cells) as well as the increase in QRS complex and QT interval durations at concentrations higher than 0.1µM in the isolated rabbit Purkinje fibres appeared to be due to a non-specific multi-ion channel blockade. Pigmentations were also seen in liver, kidney and thyroid glands in rats as well as in kidneys, liver and lymph nodes in dogs (at doses of 25mg/kg/day). Also an increase in haemosiderosis in the spleen and bone marrow as well as thymus lymphoid depletion were observed.

The toxicity after acute and chronic administration of the combination artesunate/amodiaquine was similar to that of artesunate and amodiaquine, when administered alone. In repeated dose toxicity studies, the incidence and the severity of lesions were generally related to the dose levels. Amodiaquine given alone at 30 mg/kg/day induced effects very similar to those of the 12/30 mg/kg/day artesunate amodiaquine combination.

 

Genotoxicity

Artesunate did not show any mutagenic or clastogenic potential in in vitro and in viva tests (Ames, mouse micronucleus). Although amodiaquine, like chloroquine, has shown both mutagenic and clastogenic potential, studies with the artesunate amodiaquie combination in the Ames test and micronucleus in rat did not demonstrate any evidence of genotoxicity.

 

Carcinogenesis

No studies of the carcinogenic potential of the combination of artesunate and amodiaquine or the individual agents have been conducted.

 

Toxicity to Reproduction

Reproductive toxicology studies, conducted in rats and rabbits, confirmed the known embryotoxic and teratogenic potential of artesunate and the maternal toxicity associated with amodiaquine. Subclinical artesunate exposure of male guinea pigs caused decrease in total sperm count and sperm motility and an increase in abnormal sperm cells. In the peri-postnatal study, the offspring from the F1 generation did not show any effect on sexual development, and despite an early slowing of bodyweight increases with some effect on testicular and epididymal weights, no sequelae were noted on reproductive capacity.

No new toxicity was induced through the administration of the two substances in combination.

 

Safety pharmacology studies

Slight sedative effect, a decrease in body temperature, a slight natriuretic effect and a decrease in endogenous creatinine clearance were observed with artesunate after single intravenous doses of 200 mg/kg (mice), 450 mg (rats, rabbits and dogs) and after single oral doses of 180 mg/kg in male rats. In conscious telemetered dogs, atrio-ventricular blocks and depressant effects on smooth muscles were reported from 10 mg/kg (single oral dose). Since these effects were observed only in female animals, at a low incidence and without relation to dose, the relationship to artesunate administration remains to be confirmed. Neither neurotoxicity nor prolongalon of QT(c) interval were shown.

Amodiaquine is likely to induce cardiovascular adverse effects, particularly transient prolongation of QT interval duration at 30 mg/kg administered orally. This dose level corresponds to approximately 2-fold the maximum recommended therapeutic dose. At the dose level of 100 mg/kg administered orally (about 6.7 fold the maximum recommended therapeutic dose), also slight respiratory depressant and natriuretic effects were noted.

Oral administration of both agents, amodiaquine followed by artesunate, was safe for the CNS, the cardiovascular and respiratory systems at dose levels of artesunate/amodiaquine corresponding to approximately 1.67/1.81 fold the maximum therapeutic dose levels (15/5.5 mg/kg amodiaquine/artesunate). The observed natriuretic effect on the kidney was very slight and transient.

 

6 PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Lactose anhydrous, Lactose monohydrate, croscarmellose sodium, magnesium stearate, calcium carbonate DC 95S with 5% corn starch and colloidal anhydrous silica.

 

6.2 Incompatibilities

Not applicable.

 

6.3 Shelf life

24 months

 

6.4 Special precautions for storage

Do not store above 30oC.

 

6.5 Nature and contents of container

Alu-Alu blister pack containing 3 tablets. One blister pack is contained in a carton (1 x 3).

Alu-Alu blister pack containing 6 tablets. One blister pack is contained in a carton (1 x 6).

Alu-Alu blister pack containing 3 tablets. 25 blister pack are contained in a carton (25 x 3).

Alu-Alu blister pack containing 6 tablets. 25 blister pack are contained in a carton (25 x 6).

 

6.6 Special instructions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

 

7. SUPPLIER

Cipla Limited,

Cipla House,

Peninsula Business Park, Ganpatrao Kadam Marg,

Lower Parel, Mumbai- 400013,

India

 

8. WHO REFERENCE NUMBER (PREQUALIFICATION PROGRAMME)

MA1O4

 

9. DATE OF FIRST PREQUALIFICATION/RENEWAL OF PREQUALIFICATION

8 April 2014

 

10. DATE OF REVISION OF THE TEXT

September 2014, Section 6 updated in July 2015

 

Last updated

July2015

 

References

WHO Guidelines for the Treatment of Malaria. Second edition, 2010. Available at http://whqlibdoc.who.int/publications/2010pdf

Obianime AW, Aprioku JS: Comparative study of artesunate, ACTs and their combinants on the spermatic parameters of the male guinea pig. Niger J Physiol Sci. 2009; 24(1):1-6.