Coartem

Contraindications

Hypersensitivity

Coadministration with strong CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, St. John’s wort) can result in decreased artemether and/or lumefantrine serum concentrations and loss of antimalarial efficacy

Cautions

Not approved for severe/complicated P. falciparum infections

Not approved for prevention

Concurrent CYP3A4 or CYP2D6 inhibitors / inducers

May render hormonal contraceptives ineffective

If patient vomits out drug repeatedly, use alternative treatment

Avoid with conditions that prolong QT

• Long QT syndrome, history of symptomatic cardiac disease, clinically relevant bradycardia, or severe cardiac disease
• Family history of congenital QT prolongation or sudden death
• Electrolyte imbalance (eg, hypokalemia, hypomagnesemia)
• Coadministration with other drugs that prolong QT interval (eg, class IA antiarrhythmics [quinidine, procainamide, disopyramide], or class III antiarrhythmics [amiodarone, sotalol] antiarrhythmic agents, antipsychotics [pimozide, ziprasidone], antidepressants; certain antibiotics [macrolide, fluoroquinolones], antiretrovirals [eg, ritonavir], cisapride
• CYP3A4 and CYP2D6 inhibitors may increase serum levels by inhibiting metabolism, and therefore risk for QT prolongation
• QT prolongation with other antimalarials; duplicate antimalarials should not be given concomitantly, unless there is no other treatment option, due to limited safety data
• Not for concomitant administration with halofantrine within one month of each other due to potential additive effects on QT interval
• Cautiously use quinine and quinidine for malaria following Coartem due to long half-life of Coartem and potential additive QT prolongation

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take artemether and lumefantrine with food, milk, pudding, oatmeal, or broth. The tablet may be crushed and mixed with 1 or 2 teaspoons of water for easier swallowing. You may also mix a crushed tablet with infant formula when giving this medication to a child. Start eating normally as soon as possible to help your body better absorb the medication.

If you vomit within 1 hour after taking this medication, take another dose. If your vomiting continues or you cannot eat, call your doctor.

Artemether and lumefantrine is usually given as a total of 6 doses over a period of 3 days. Carefully follow your doctor's instructions about how many tablets to take per dose. Artemether and lumefantrine doses are based on weight and age. The usual doses are as follows, unless your doctor tells you otherwise.

For people over 16 years old who weigh at least 77 pounds:

• Take four (4) tablets as an initial dose.

• Take 4 more tablets 8 hours later.

• Take 4 tablets in the morning and 4 tablets in the evening for the next 2 days.

For children younger than 16 years old who weigh between 55 and 77 pounds:

• Take three (3) tablets as an initial dose.

• Take 3 more tablets 8 hours later.

• Take 3 tablets in the morning and 3 tablets in the evening for the next 2 days.

For children younger than 16 years old who weigh between 33 and 55 pounds:

• Take two (2) tablets as an initial dose.

• Take 2 more tablets 8 hours later.

• Take 2 tablets in the morning and 2 tablets in the evening for the next 2 days.

For children younger than 16 years old who weigh between 11 and 33 pounds:

• Take one (1) tablet as an initial dose.

• Take a second tablet 8 hours later.

• Take 1 tablet in the morning and 1 tablet in the evening for the next 2 days.

No medication is 100% effective in treating malaria. For best results, keep using the medication as directed.

Call your doctor if your symptoms do not improve, or if you have a fever, chills, headache, or muscle pain.

Store at room temperature away from moisture and heat.

• Artemether/lumefantrine is a fixed combination of 2 antimalarial agents.1 Artemether is an artemisinin-derivative antimalarial;1 161 lumefantrine is an aryl aminoalcohol antimalarial.161 Both drugs are blood schizonticidal agents active against erythrocytic stages of Plasmodium.1

• Artemether is rapidly metabolized to an active metabolite (dihydroartemisinin; DHA).1 Antimalarial activity of artemether and dihydroartemisinin has been attributed to the endoperoxide moiety.1

• Exact mechanism by which lumefantrine exerts its antimalarial effect not well defined;1 available data suggest the drug inhibits formation of β-hematin by forming a complex with hemin.1

• Both artemether and lumefantrine inhibit nucleic acid and protein synthesis.1

• Artemether has rapid onset of action and the drug and its metabolite have elimination half-lives of about 2 hours; lumefantrine has a longer elimination half-life (about 3–6 days).3 6 The rationale behind the fixed-combination preparation is that the artemisinin derivative (artemether) provides rapid resolution of symptoms by reducing the number of malaria parasites and then lumefantrine clears any residual parasites.3 6 161

• Although clinical importance not known, P. falciparum with decreased susceptibility to artemether or lumefantrine can be selected in vitro or in vivo.1 Use of the artemisinin-based combinations may delay or prevent emergence of resistance.161

It is important that your doctor check your progress after treatment. This is to make sure that the infection is cleared up completely, and to allow your doctor to check for any unwanted effects.

If your symptoms do not improve within a few days or if they become worse, check with your doctor.

Tell your doctor if you have used other medicines to treat your malaria infection. Using this medicine together with halofantrine (Halfan®), mefloquine (Lariam®), or quinine may increase the chance for more serious side effects.

This medicine can cause changes in heart rhythms, such as a condition called QT prolongation. It may change the way your heart beats and cause fainting or serious side effects in some patients. Call your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

Check with your doctor right away if you have flu-like symptoms (such as chills, fever, headache, or muscle pains) again after treatment with this medicine.

This medicine may cause serious allergic reactions. Call your doctor right away if you have a rash, itching, hives, hoarseness, trouble with breathing, trouble with swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Malaria is spread by the bites of certain kinds of infected female mosquitoes. If you are living in or will be traveling to an area where there is a chance of getting malaria, the following mosquito-control measures will help to prevent infection:

• If possible, avoid going out between dusk and dawn because it is at these times that mosquitoes most commonly bite.
• Wear long-sleeved shirts and long trousers to protect your arms and legs, especially from dusk through dawn when mosquitoes are out.
• Apply insect repellant, preferably one containing DEET, to uncovered areas of the skin from dusk through dawn when mosquitoes are out.
• If possible, sleep in a screened or air-conditioned room or under mosquito netting sprayed with insecticide to avoid being bitten by malaria-carrying mosquitoes.
• Use mosquito coils or sprays to kill mosquitoes in living and sleeping quarters during evening and nighttime hours.

This medicine may decrease the effects of birth control pills or transdermal patches. To avoid an unwanted pregnancy, it is a good idea to use additional contraceptive measures with your pills or patches (e.g., condoms, a diaphragm, or a contraceptive foam or jelly) while using this medicine.

Grapefruits and grapefruit juice may increase the effects of artemether and lumefantrine combination by increasing the amount of this medicine in your body. You should not eat grapefruit or drink grapefruit juice while you taking this medicine.

Do not take other medicines, including prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements, unless they have been discussed with your doctor. Artemether and lumefantrine combination should not be taken with certain other medicines, including carbamazepine (Tegretol®), phenytoin (Dilantin®), rifampin (Rifadin®, Rimactane®), or St. John's wort.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• chills
• cough
• fast, irregular, pounding, or racing heartbeat or pulse
• fever
• headache
• muscle aches
• pale skin
• right upper abdominal or stomach pain and fullness
• sore throat
• stuffy or runny nose
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Accumulation of pus
• acid or sour stomach
• belching
• black, tarry stools
• bladder pain
• blood in the urine
• bloody or cloudy urine
• body aches or pain
• change in hearing
• chest pain
• cloudy urine
• convulsions
• cough producing mucus
• decreased urine
• diarrhea
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with swallowing
• dizziness
• dry mouth
• ear congestion
• ear drainage
• earache or pain in the ear
• frequent urge to urinate
• general feeling of discomfort or illness
• heartburn
• increased thirst
• indigestion
• joint pain
• loss of appetite
• loss of voice
• lower back or side pain
• mood changes
• muscle pain or cramps
• nasal congestion
• nausea or vomiting
• noisy breathing
• numbness or tingling in the hands, feet, or lips
• red rash with watery, yellow-colored, or pus filled blisters
• shivering
• shortness of breath
• sneezing
• sores, ulcers, or white spots on the lips or in the mouth
• stomach discomfort, upset, or pain
• sweating
• swollen glands
• swollen, red, tender area of infection
• thick yellow to honey-colored crusts
• tightness in the chest
• troubled with sleeping

• Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty with moving
• lack or loss of strength
• muscle aching or cramping
• muscle pain or stiffness
• sleeplessness
• unable to sleep
• weight loss

• Back pain
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• burning, dry, or itching eyes
• continuing ringing or buzzing or other unexplained noise in the ears
• difficulty having a bowel movement (stool)
• discharge or excessive tearing
• dizziness or lightheadedness
• feeling of constant movement of self or surroundings
• hearing loss
• hives or welts
• redness of the skin
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• sensation of spinning
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• trembling or shaking of the hands or feet
• uncontrolled eye movements
• unsteadiness, trembling, or other problems with muscle control or coordination

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Dizziness.
• Fever or chills.
• Upset stomach or throwing up.
• Belly pain.
• Not hungry.
• Feeling tired or weak.
• Muscle or joint pain.
• Not able to sleep.
• Cough.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Coartem (artemether/lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above. Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported [see Clinical Studies (14.1)].

Limitations of Use:

• Coartem Tablets are not approved for patients with severe or complicated P. falciparum malaria.
  
• Coartem Tablets are not approved for the prevention of malaria.

Hypersensitivity

• Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets [see Adverse Reactions (6.3)].

Strong CYP3A4 Inducers

• Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John’s wort with Coartem Tablets can result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Warnings and Precautions (5.3), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

     Prolongation of the QT Interval

Some antimalarials (e.g., halofantrine, quinine, quinidine) including Coartem Tablets have been associated with prolongation of the QT interval on the electrocardiogram.

Coartem Tablets should be avoided in patients:

• with congenital prolongation of the QT interval (e.g., long QT syndrome) or any other clinical condition known to prolong the QTc interval such as patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
  
• with a family history of congenital prolongation of the QT interval or sudden death.
  
• with known disturbances of electrolyte balance, e.g., hypokalemia or hypomagnesemia.
  
• receiving other medications that prolong the QT interval, such as class IA (quinidine, procainamide, disopyramide), or class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents) [see Clinical Pharmacology (12.6)].
  
• receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

     Use of QT Prolonging Drugs and Other Antimalarials

Halofantrine and Coartem Tablets should not be administered within 1 month of each other due to the long elimination half-life of lumefantrine (3 to 6 days) and potential additive effects on the QT interval [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Antimalarials should not be given concomitantly with Coartem Tablets, unless there is no other treatment option, due to limited safety data.

Drugs that prolong the QT interval, including antimalarials such as quinine and quinidine, should be used cautiously following Coartem Tablets, due to the long elimination half-life of lumefantrine (3 to 6 days) and the potential for additive effects on the QT interval; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Warnings and Precautions (5.1), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

If mefloquine is administered immediately prior to Coartem Tablets there may be a decreased exposure to lumefantrine, possibly due to a mefloquine-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets [see Dosage and Administration (2.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].

     Drug Interactions with CYP3A4

When Coartem Tablets are coadministered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are coadministered with an inhibitor of CYP3A4, including grapefruit juice it may result in increased concentrations of artemether and/or lumefantrine and potentiate QT prolongation. When Coartem Tablets are coadministered with inducers of CYP3A4 it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Contraindications (4) and Drug Interactions (7)].

Drugs that have a mixed effect on CYP3A4, especially antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets [see Drug Interactions (7.3, 7.7)].

Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see Drug Interactions (7.5)].

     Drug Interactions with CYP2D6

Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the coadministered 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 Coartem Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

     Recrudescence

Food enhances absorption of artemether and lumefantrine following administration of Coartem Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [see Dosage and Administration (2.1)].

In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug.

     Hepatic and Renal Impairment

Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [see Dosage and Administration (2.4)].

     Plasmodium vivax Infection

Coartem Tablets have been shown in limited data (43 patients) to be effective in treating the erythrocytic stage of P. vivax infection. However, relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoites forms that may remain dormant in the liver.

There is no information on overdoses of Coartem Tablets higher than the doses recommended for treatment.

In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.

Coartem (artemether/lumefantrine) Tablets

20 mg/120 mg Tablets - yellow, round flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other.

Bottle of 24                         NDC 0078-0568-45

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].

Dispense in tight container (USP).