QUALITATIVE AND QUANTITATIVE COMPOSITION

Qmetem Tablets 20mg+120mg
Each tablet contains:
Artemether USP ……………. 20mg
Lumefantrine USP …. 120mg
(Product Specs.: Ph. Int.)
“Product contains lactose”

Qmetem DS Tablets 40mg+240mg
Each tablet contains:
Artemether USP………40mg
Lumefantrine USP…….240mg
(Product Specs.: Ph. Int.)
“Product contains lactose”

Qmetem Plus DS Tablets 80mg+480mg
Each tablet contains:
Artemether USP………80mg
Lumefantrine USP…….480mg
(Product Specs.: Ph. Int.)

Qmetem Plus Dry Suspension 15mg+90mg/5mL
Each 5mL contains:
Artemether USP………15mg
Lumefantrine USP…….90mg
(Product Specs.: Ph. Int.)

Qmetem Plus DS Suspension 30mg+180mg/5mL
Each 5mL contains:
Artemether USP………30mg
Lumefantrine USP…….180mg
(Product Specs.: Ph. Int.)

PHARMACEUTICAL FORM
Tablets and Powder for Oral suspension

CLINICAL PARTICULARS

Therapeutic Indications
Qmetem is a combination of artemether and lumefantrine which acts as blood schizontocides and is indicated for the treatment of acute uncomplicated

Plasmodium falciparum malaria in adults, children and infants of 5 kg and above.

Posology and method of administration
Posology

Tablets:
Adults and children weighing 35 kg and above:
For patients 12 years of age and above and 35 kg body weight and above, a course of treatment comprises six doses of four tablets i.e. a total of 24 tablets, given over a period of 60 hours as follows:

• The first dose of four tablets, given at the time of initial diagnosis, should be followed by five further doses of four tablets given at 8, 24, 36, 48 and 60 hours thereafter.

Children and infants weighing 5 kg to less than 35 kg:
A six-dose regimen is recommended with 1 to 3 tablets per dose, depending on body weight:

• 5 to less than 15 kg bodyweight: The first dose of one tablet, given at the time of initial diagnosis, should be followed by five further doses of one tablet given at 8, 24, 36, 48, and 60 hours thereafter.
• 15 to less than 25 kg bodyweight: The first dose of two tablets, given at the time of initial diagnosis, should be followed by five further doses of two tablets given at 8, 24, 36, 48, and 60 hours thereafter.
• 25 to less than 35 kg bodyweight: The first dose of three tablets, given at the time of initial diagnosis, should be followed by five further doses of three tablets given at 8, 24, 36, 48, and 60 hours thereafter.

Infants weighing less than 5 kg: The safety and efficacy have not been established in infants weighing less than 5 kg and no dosing recommendations can be made.

Older age group: No information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.

Suspension:

Body Weight (Kg)		Day 1	Day 2		Day 3
	Qmetem Plus DS	Qmetem Plus	Qmetem Plus DS	Qmetem Plus	Qmetem Plus DS	Qmetem Plus
5 kg	3.5mL	7 mL	3.5mL	7 mL	3.5mL	7 mL
7.5 kg	5 mL	10mL	5 mL	10mL	5 mL	10mL
10 kg	7 mL	14 mL	7 mL	14 mL	7 mL	14 mL
15 kg	10mL	20mL	10mL	20mL	10mL	20mL

Method of administration
Tablets
To increase absorption, tablets should be taken with food or a milky drink. If patients are unable to tolerate food, tablets should be administered with water, but the systemic exposure may be reduced Patients who vomit within 1 hour of taking the medication should repeat the dose.

Direction for Preparation of Suspension:
Add a small quantity of cool boiled water in the bottle and shake until all the powder is dispersed, then slowly add more water up to the mark given on the label and shake vigorously after tightening the cap.

Contraindications

• Patients with known hypersensitivity to the active substance.
• Patients with severe malaria according to WHO definition.
• Patients who are taking any drug which is metabolized by the cytochrome enzyme CYP2D6 (e.g. 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 (proarrhythmic). These drugs include:
• Antiarrhythmics of classes IA and III,
• Neuroleptics, antidepressive agents,
• Certain antibiotics including some agents of the following classes: Macrolides, fluoroquinolones, imidazole and triazole antifungal agents,
• Certain non-sedating antihistamines (terfenadine, astemizole), Cisapride, Flecainide
• Patients with a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
• Patients with disturbances of electrolyte balance e.g. hypokalemia or hypomagnesaemia.
• Patients taking drugs that are strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, St. John’s wort.

Special warnings and precautions for use

• It is not recommended during the first trimester of pregnancy in situations where other suitable and effective antimalarial are available. It should not be given concurrently with any other antimalarial agent
• If a patient deteriorates whilst taking the medicine, alternative treatment for malaria should be started without delay. In such cases, monitoring of the ECG is recommended and steps should be taken to correct any electrolyte disturbances.
• If quinine is given after artemether+ lumefantrine, close monitoring of the ECG is advised.
• If Artemether+lumefantrine is given after mefloquine, close monitoring of food intake is advised.
• In patients previously treated with halofantrine, artemether+ lumefantrine should not be administered earlier than one month after the last halofantrine dose.
• Like other antimalarials (e.g. halofantrine, quinine and quinidine) Artemether+lumefantrine has the potential to cause QT prolongation.
• Caution is recommended when combining this medicine with drugs exhibiting variable patterns of inhibition, moderate induction or competition for CYP3A4 as the therapeutic effects of some drugs could be altered. Drugs that have a mixed inhibitory/induction effect on CYP3A4, especially anti-retroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors should be used with caution in patients taking this medication.

Interaction with other medicinal products and other forms of interaction.
Contraindications of concomitant use

Interaction with drugs that are known to prolong the QTc interval
It is contraindicated with concomitant use of drugs (they may cause prolonged QTc interval and Torsade de Pointes) such as: Antiarrhythmic 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, flecainide.

Interaction with drugs metabolized by CYP2D6
Co-administration of Artemether+lumefantrine with drugs that are metabolized by this iso-enzyme is contraindicated (e.g. neuroleptics, metoprolol, and tricyclic antidepressants such as imipramine, amitriptyline, clomipramine) is contraindicated.

Interaction with strong inducers of CYP3A4 such as rifampin
Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, St. John’s Wort is contraindicated with Artemether+lumefantrine. Inducers should not be administered at least one month after administration of this medicine, unless critical to use as judged by the prescriber.

Concomitant use not recommended
Interaction with other antimalarial drugs
It should not be given concurrently with other antimalarials unless there is no other treatment option.

Mefloquine
Pre-treatment with mefloquine had no effect on plasma concentrations of artemether or the artemether/dihydroartemisinin ratio but there was a significant reduction in plasma levels of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be encouraged to eat at dosing times to compensate for the decrease in bioavailability.

Quinine
It would appear that the inherent risk of QTc prolongation associated with I.V. quinine was enhanced by prior administration of Artemether+lumefantrine.

Concomitant use requiring caution
Interaction with CYP3A4 inhibitors
Artemether is metabolized predominantly by the cytochrome enzyme CYP3A4, but do not inhibit this enzyme at therapeutic concentrations.

Ketoconazole
Artemether+lumefantrine should be used cautiously with drugs due to potential for increased concentrations of lumefantrine which could lead to QT prolongation.

Interaction with weak to moderate inducers of CYP3A4
When Artemether+lumefantrine is co-administered with moderate inducers of CYP3A4, it may result in decreased concentrations and loss of antimalarial efficacy.

Interaction with anti-retroviral drugs such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors
Artemether+lumefantrine should be used cautiously in patients on ARTs since decreased concentrations may result in a decrease of antimalarial efficacy and increased lumefantrine concentrations may cause QT prolongation.

Lopinavir/ ritonavir
Exposures to lopinavir/ritonavir are not significantly affected by concomitant use.

Nevirapine
Lumefantrine Cmax and AUC were non-significantly reduced by nevirapine.

Efavirenz
Exposures to efavirenz were not significantly affected by concomitant use.

Interactions resulting in effects of Artemether + lumefantrine on other drugs
Interaction with hormonal contraceptives
Artemether+lumefantrine may potentially reduce the effectiveness of hormonal contraceptives. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control for about one month.

Drug-food/drink interactions
It should be taken with food or drinks rich in fat such as milk as the absorption of both Artemether+lumefantrine is increased. Grapefruit juice should be used cautiously during treatment.

Fertility, Pregnancy and lactation
Fertility
There is no information on the effects on human fertility.

Pregnancy
Treatment is not recommended during the first trimester of pregnancy in situations where other suitable and effective antimalarial are available, however, it should not be withheld in life-threatening situations, where no other effective antimalarial are available.

During the second and third trimester, treatment should be considered if the expected benefit to the mother outweighs the risk to the fetus.

Lactation
It is recommended that breast- feeding should not resume until at least one week after the last dose, unless potential benefits to the mother and child outweigh the risks of Artemether+lumefantrine treatment.

Effects on ability to drive and use machines
Patients receiving Artemether+lumefantrine should be warned that dizziness or fatigue/ asthenia may occur in which case they should not drive or use machines.

Undesirable effects
Adverse reactions are ranked under headings of frequency using the MedDRA frequency convention: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from available data).

	Adults and adolescents above 12 years of age	Infants and children of 12 years of age and below (incidence estimates)
Blood and lymphatic system disorders
Delayed hemolytic anemia	Not Known	Not Known
Immune system disorders
Hypersensitivity	Not known	Rare
Metabolism and nutrition disorders
Decreased appetite	Very common	Very common (16.8 %)
Psychiatric disorders
Sleep disorders	Very common	Common (6.4 %)
Insomnia	Common	Uncommon
Nervous system disorders
Headache	Very common	Very common (17.1 %)
Dizziness	Very common	Common (5.5 %)
Paresthesia	Common	—
Ataxia, hypoesthesia	Uncommon	—
Somnolence	Uncommon	Uncommon
Clonus	Common	Uncommon
Cardiac disorders
Palpitations	Very common	Common (1.8 %)
Electrocardiogram QT prolonged	Common	Common (5.3 %)
Respiratory, thoracic and mediastinal disorders
Cough	Common	Very common (22.7 %)
Gastrointestinal disorders
Vomiting	Very common	Very common (20.2 %)
Abdominal pain	Very common	Very common (12.1 %)
Nausea	Very common	Common (6.5 %)
Diarrhea	Common	Common (8.4 %)
Hepatobiliary disorders
Liver function tests increased	Uncommon	Common (4.1 %)
Skin and subcutaneous tissue disorders
Rash	Common	Common (2.7 %)
Pruritus & urticaria	Common	Uncommon
Angioedema	Not known	Not known
Musculoskeletal and connective tissue disorders
Arthralgia	Very common	Common (2.1 %)
Myalgia	Very common	Common (2.2 %)
General disorders and administration site conditions
Asthenia	Very common	Common (5.2 %)
Fatigue	Very common	Common (9.2 %)
Gait disturbance	Common	—

Overdose
In cases of suspected over dosage symptomatic and supportive therapy should be given as appropriate, which should include ECG and blood potassium monitoring.

PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: Antimalarials, blood schizonticide,
ATC code: P01BF01

Pharmacodynamic properties
The Artemether+lumefantrine combination comprises a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively. The site of antiparasitic action of both components is the food vacuole of the malarial parasite, where they are thought to interfere with the conversion of heme, a toxic intermediate produced during hemoglobin breakdown, to the nontoxic hemozoin, 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 heme iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid and protein synthesis within the malarial parasite. Combination has been reported to have potent activity in terms of clearing gametocytes.

Pharmacokinetic properties
Pharmacokinetic characterization is limited by the lack of an intravenous formulation, and the very high inter-and intra- subject variability of Artemether+lumefantrine plasma concentrations and derived pharmacokinetic parameters (AUC, Cmax).

Absorption
Artemether is absorbed fairly rapidly and dihydroartemisinin, the active metabolite of Artemether+lumefantrine, appears rapidly in the systemic circulation with peak plasma concentrations of both compounds reached about 2 hours after dosing. Food enhances the absorption of both artemether and lumefantrine.

Food has also been shown to increase the absorption of lumefantrine in patients with malaria, although to a lesser extent (approximately two-fold), most probably due to the lower fat content of the food ingested by acutely ill patients. Patients should therefore be encouraged to take the medication with a normal diet as soon as food can be tolerated.

Distribution
Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47–76%).

Biotransformation
Artemether is rapidly and extensively metabolized (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolize Artemether+lumefantrine to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly through the isoenzyme CYP3A4/5.

Elimination
Artemether and dihydroartemisinin are rapidly cleared from plasma with a terminal half-life of about 2 hours. Lumefantrine is eliminated very slowly with an elimination half-life of 2 to 6 days.

PHARMACEUTICAL PROPERTIES
Incompatibilities
Not applicable

Shelf life: 02 years

SPECIAL PRECAUTIONS FOR STORAGE/INSTRUCTIONS

• Once reconstituted the suspension must be used within 14 days when stored in the refrigerator or within 7 days at room temperature.
• Protect from heat, light & moisture, store below 30°C.
• The expiration date refers to the product correctly stored at the required condition.
• Do not take if seal is broken. Close the bottle properly after use.
• Keep out of the reach of children.
• To be sold on the prescription of a registered medical practitioner only.

NATURE AND CONTENTS OF CONTAINER/PRESENTATION:
Qmetem Tablets 20mg+120mg: Pack of 16’s
Qmetem DS Tablets 40mg+240mg: Pack of 8’s.
Qmetem DS Plus Tablets 80mg+480mg: Pack of 6’s
Qmetem Plus Dry Suspension 15mg+90mg/5mL (60mL) in 90mL Amber Glass Bottle
Qmetem Plus Dry Suspension 15mg+90mg/5mL (30mL) in 60mL Amber Glass Bottle
Qmetem Plus DS Suspension 30mg+180mg/5mL (30mL) in 60mL Amber Glass Bottle

REGISTRATION HOLDER / MARKETING AUTHORIZATION HOLDER
Head Office:
Bosch Pharmaceuticals (Pvt.) Ltd.,
8, Modern Society, Tipu Sultan Road, Karachi, Pakistan

Manufacturer:
Bosch Pharmaceuticals (Pvt.) Ltd.,
Plot No. 221-223, Sector 23, Korangi Industrial area, Karachi, Pakistan

REGISTRATION / MARKETING AUTHORIZATION NUMBER
Qmetem Tablets 20mg+120mg: 050506
Qmetem DS Tablets 40mg+240mg: 061699
Qmetem Plus DS Tablets 80mg+480mg: 067515
Qmetem Plus Dry Suspension 15mg+90mg/5mL: 067122
Qmetem Plus DS Suspension 30mg+180mg/5mL: 080296

DATE FROM WHICH MARKETING IS AUTHORIZED/RENEWAL OF AUTHORIZATION
Qmetem Tablets 20mg+120mg: 27-08-2008/26-08-2023
Qmetem DS Tablets 40mg+240mg: 15-07-2010/14-07-2020
Qmetem Plus DS Tablets 80mg+480mg: 05-04-2011/04-04-2021
Qmetem Plus Dry Suspension 15mg+90mg/5mL: 30-11-2010/29-11-2020
Qmetem Plus DS Suspension 30mg+180mg/5mL:16-03-2016/15-03-2021

DATE OF REVISION OF THE TEXT.
23-02-24