COARTEM (Page 2 of 7)

5.4 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)].

5.5 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.

5.6 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)].

5.7 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.

6 ADVERSE REACTIONS

The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:

• Hypersensitivity Reactions [see Contraindications (4)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.1)]
• Use of QT Prolonging Drugs and Other Antimalarials [see Warnings and Precautions (5.2)]
• Drug Interactions with CYP3A4 [see Warnings and Precautions (5.3)]
• Drug Interactions with CYP2D6 [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.

The data described below reflect exposure to a 6-dose regimen of Coartem Tablets in 1979 patients including 647 adults (older than 16 years) and 1332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and noncontrolled, open-label trials (1613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.

Tables 1 and 2 show the most frequently reported adverse reactions (greater than or equal to 3%) in adults and children respectively who received the 6-dose regimen of Coartem Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline, but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.

In limited comparative studies, the adverse reaction profile of Coartem Tablets appeared similar to that of another antimalarial regimen.

Discontinuation of Coartem Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1332) in children.

Table 1: Adverse Reactions Occurring in 3% or More of Adult Patients Treated in Clinical Trials With the 6-dose Regimen of Coartem Tablets

*Adult patients defined as greater than 16 years of age.
System Organ Class	Preferred Term	Adults* N = 647 (%)
Nervous system disorders	Headache	360 (56)
	Dizziness	253 (39)
Metabolism and nutrition disorders	Anorexia	260 (40)
General disorders and administration site conditions	Asthenia	243 (38)
	Pyrexia	159 (25)
	Chills	147 (23)
	Fatigue	111 (17)
	Malaise	20 (3)
Musculoskeletal and connective tissue disorders	Arthralgia	219 (34)
	Myalgia	206 (32)
Gastrointestinal disorders	Nausea	169 (26)
	Vomiting	113 (17)
	Abdominal pain	112 (17)
	Diarrhea	46 (7)
Psychiatric disorders	Sleep disorder	144 (22)
	Insomnia	32 (5)
Cardiac disorders	Palpitations	115 (18)
Hepatobiliary disorders	Hepatomegaly	59 (9)
Blood and lymphatic system disorders	Splenomegaly	57 (9)
	Anemia	23 (4)
Respiratory, thoracic and mediastinal disorders	Cough	37 (6)
Skin and subcutaneous tissue disorders	Pruritus	24 (4)
	Rash	21 (3)
Ear and labyrinth disorders	Vertigo	21 (3)
Infections and infestations	Malaria	18 (3)
	Nasopharyngitis	17 (3)

Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials With the 6-dose Regimen of Coartem Tablets

*Children defined as patients less than or equal to 16 years of age.
System Organ Class	Preferred Term	Children* N = 1332 (%)
General disorders and administration site conditions	Pyrexia	381 (29)
	Chills	72 (5)
	Asthenia	63 (5)
	Fatigue	46 (3)
Respiratory, thoracic and mediastinal disorders	Cough	302 (23)
Gastrointestinal disorders	Vomiting	242 (18)
	Abdominal pain	112 (8)
	Diarrhea	100 (8)
	Nausea	61 (5)
Infections and infestations	Plasmodium falciparum infection	224 (17)
	Rhinitis	51 (4)
Metabolism and nutrition disorders	Anorexia	175 (13)
Nervous system disorders	Headache	168 (13)
	Dizziness	56 (4)
Blood and lymphatic system disorders	Splenomegaly	124 (9)
	Anemia	115 (9)
Hepatobiliary disorders	Hepatomegaly	75 (6)
Investigations	Aspartate aminotransferase increased	51 (4)
Musculoskeletal and connective tissue disorders	Arthralgia	39 (3)
	Myalgia	39 (3)
Skin and subcutaneous tissue disorders	Rash	38 (3)

Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem Tablets, which occurred in clinical studies at less than 3% regardless of causality are listed below:

Blood and Lymphatic System Disorders: eosinophilia

Ear and Labyrinth Disorders: tinnitus

Eye Disorders: conjunctivitis

Gastrointestinal Disorders: constipation, dyspepsia, dysphagia, peptic ulcer

General Disorders: gait disturbance

Infections and Infestations: abscess, acrodermatitis, bronchitis, ear infection, gastroenteritis, helminthic infection, hook-worm infection, impetigo, influenza, lower respiratory tract infection, malaria, nasopharyngitis, oral herpes, pneumonia, respiratory tract infection, subcutaneous abscess, upper respiratory tract infection, urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, hematocrit decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white blood cell count decreased, white blood cell count increased

Metabolism and Nutrition Disorders: hypokalemia

Musculoskeletal and Connective Tissue Disorders: back pain

Nervous System Disorders: ataxia, clonus, fine motor delay, hyperreflexia, hypoesthesia, nystagmus, tremor

Psychiatric Disorders: agitation, mood swings

Renal and Urinary Disorders: hematuria, proteinuria

Respiratory, Thoracic and Mediastinal Disorders: asthma, pharyngo-laryngeal pain

Skin and Subcutaneous Tissue Disorders: urticaria