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DRUGS & SUPPLEMENTS
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What are the side effects you encounter while taking this medicine? |
Anther (artemether/lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above. Anther 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 :
5 to <15 kg | 1 tablet |
15 to <25 kg | 2 tablets |
25 to <35 kg | 3 tablets |
35 kg and over | 4 tablets |
Anther Tablets should be taken with food. Patients with acute malaria are frequently averse to food. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of Anther and lumefantrine.
For patients who are unable to swallow the tablets such as infants and children, Anther Tablets may be crushed and mixed with a small amount of water (1 to 2 teaspoons) in a clean container for administration immediately prior to use. The container can be rinsed with more water and the contents swallowed by the patient. The crushed tablet preparation should be followed whenever possible by food/drink (e.g., milk, formula, pudding, broth, and porridge).
In the event of vomiting within 1 to 2 hours of administration, a repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment.
A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a bodyweight of 35 kg and above:
Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice-daily (morning and evening) for the following 2 days (total course of 24 tablets).
For patients weighing less than 35 kg, see Dosage in Pediatric Patients (2.3).
A 3-day treatment schedule with a total of 6 doses is recommended as below:
5 kg to less than 15 kg bodyweight: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice-daily for the following 2 days (total course of 6 tablets).
15 kg to less than 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice-daily (morning and evening) for the following 2 days (total course of 12 tablets).
25 kg to less than 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice-daily (morning and evening) for the following 2 days (total course of 18 tablets).
35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice-daily (morning and evening) for the following 2 days (total course of 24 tablets).
No specific pharmacokinetic studies have been carried out in patients with hepatic or renal impairment. Most patients with acute malaria present with some degree of related hepatic and/or renal impairment. In clinical studies, the adverse event profile did not differ in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. No specific dose adjustments are needed for patients with mild or moderate hepatic impairment.
In clinical studies, the adverse event profile did not differ in patients with mild or moderate renal impairment compared to patients with normal renal function. There were few patients with severe renal impairment in clinical studies. There is no significant renal excretion of lumefantrine, Anther and dihydroartemisinin (DHA) in healthy volunteers and while clinical experience in this population is limited, no dose adjustment is recommended.
Caution should be exercised when administering Anther Tablets in patients with severe hepatic or renal impairment .
Anther Tablets contain 20 mg of Anther and 120 mg of lumefantrine. Anther Tablets are supplied as 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 side.
Tablets are scored and contain 20 mg Anther and 120 mg lumefantrine. (3)
Hypersensitivity
Strong CYP3A4 Inducers
Some antimalarials (e.g., halofantrine, quinine, quinidine) including Anther Tablets have been associated with prolongation of the QT interval on the electrocardiogram.
Anther Tablets should be avoided in patients:
Halofantrine and Anther Tablets should not be administered within 1 month of each other due to the long elimination half-life of lumefantrine 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 Anther 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 Anther 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 Anther 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 Anther Tablets [see Dosage and Administration (2.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].
When Anther Tablets are coadministered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Anther Tablets are coadministered with an inhibitor of CYP3A4, including grapefruit juice it may result in increased concentrations of Anther and/or lumefantrine and potentiate QT prolongation. When Anther Tablets are coadministered with inducers of CYP3A4 it may result in decreased concentrations of Anther and/or lumefantrine and loss of antimalarial efficacy .
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 Anther Tablets .
Anther 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 .
Administration of Anther 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 Anther Tablets due to the potential additive effect on the QT interval .
Food enhances absorption of Anther and lumefantrine following administration of Anther Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater .
In the event of recrudescent P. falciparum infection after treatment with Anther Tablets, patients should be treated with a different antimalarial drug.
Anther Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment .
Anther 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.
The most common adverse reactions in adults are headache, anorexia, dizziness, asthenia, arthralgia and myalgia. The most common adverse reactions in children (>12%) are pyrexia, cough, vomiting, anorexia, and headache. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:
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 Anther Tablets in 1,979 patients including 647 adults and 1,332 children (16 years and younger). For the 6-dose regimen, Anther Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Anther Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) 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 (≥3%) in adults and children respectively who received the 6-dose regimen of Anther 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 Anther Tablets appeared similar to that of another antimalarial regimen.
Discontinuation of Anther 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% (21/1,332) in children.
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) |
* Adult patients defined as >16 years of age
System Organ Class | Preferred Term | Children* N=1,332 (%) |
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) |
* Children defined as patients ≤16 years of age
Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Anther Tablets which occurred in clinical studies at <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, hookworm 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
The following adverse reactions have been identified during post-approval use of Anther Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Oral administration of rifampin, a strong CYP3A4 inducer, with Anther Tablets resulted in significant decreases in exposure to Anther, dihydroartemisinin (DHA, metabolite of Anther) and lumefantrine by 89%, 85% and 68%, respectively, when compared to exposure values after Anther Tablets alone. Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John’s wort is contraindicated with Anther Tablets [see Contraindications (4) and Clinical Pharmacology (12.3)].
Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Anther Tablets resulted in a moderate increase in exposure to Anther, DHA, and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Anther Tablets is necessary when administered with ketoconazole or other potent CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Anther Tablets should be used cautiously with drugs that inhibit CYP3A4 [see Warnings and Precautions and Clinical Pharmacology (12.3)].
Both Anther and lumefantrine are metabolized by CYP3A4. Antiretroviral drugs, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. Therefore, the effects of antiretroviral drugs on the exposure to Anther, DHA, and lumefantrine are also variable . Anther Tablets should be used cautiously in patients on antiretroviral drugs because decreased Anther, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Anther Tablets, and increased lumefantrine concentrations may cause QT prolongation .
Administration of 3 doses of mefloquine followed 12 hours later by a 6-dose regimen of Anther Tablets in 14 healthy volunteers demonstrated no effect of mefloquine on plasma concentrations of Anther or the artemether/DHA ratio. However, exposure to lumefantrine was reduced, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of Anther Tablets [see Warnings and Precautions and Clinical Pharmacology (12.3)].
In vitro, the metabolism of ethinyl estradiol and levonorgestrel was not induced by Anther, DHA, or lumefantrine. However, Anther has been reported to weakly induce, in humans, the activity of CYP2C19, CYP2B6, and CYP3A. Therefore, Anther Tablets 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
Lumefantrine inhibits CYP2D6 in vitro. Administration of Anther 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 Anther Tablets due to the potential additive effect on the QT interval [see Warnings and Precautions (5.1, 5.4) and Clinical Pharmacology (12.3)].
A single dose of intravenous quinine (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of Anther Tablets demonstrated no effect of intravenous quinine on the systemic exposure of DHA or lumefantrine. Quinine exposure was also not altered. Exposure to Anther was decreased. This decrease in Anther exposure is not thought to be clinically significant. However, quinine and other drugs that prolong the QT interval should be used cautiously following treatment with Anther Tablets due to the long elimination half-life of lumefantrine and the potential for additive QT effects; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Anther Tablets are to be used with caution when coadministered with drugs that may cause prolonged QT interval such as antiarrhythmics 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 .
Pregnancy Category C
Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Anther Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.
The efficacy of Anther Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.
Anther Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnant rats dosed during the period of organogenesis at or higher than a dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about 3 times the clinical dose (based on body surface area comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at 2 times the clinical dose. Embryo-fetal loss is a significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, Anther exposures in animals may not be predictive of human exposures . These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.
It is not known whether Anther or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Anther Tablets are administered to a nursing woman. Animal data suggest both Anther and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to Anther and lumefantrine through breast milk.
The safety and effectiveness of Anther Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more . The safety and efficacy have not been established in pediatric patients who weigh less than 5 kg. Children from non-endemic countries were not included in clinical trials.
Clinical studies of Anther Tablets did not include sufficient numbers of subjects aged 65 years and over to determine they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Anther Tablets.
No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Anther Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, Anther and DHA, no dose adjustment for the use of Anther Tablets in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment .
There is no information on overdoses of Anther 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.
Anther Tablets contain a fixed combination of 2 antimalarial active ingredients, Anther, an artemisinin derivative, and lumefantrine. Both components are blood schizontocides. The chemical name of Anther is (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepine. Anther is a white, crystalline powder that is freely soluble in acetone, soluble in methanol and ethanol, and practically insoluble in water. It has the empirical formula C16H26O5 with a molecular weight of 298.4, and the following structural formula:
The chemical name of lumefantrine is (1RS)-2-(dibutylamino)-1-{(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-9H-fluorene-4-yl}ethanol. Lumefantrine is a yellow, crystalline powder that is freely soluble in N,N-dimethylformamide, chloroform, and ethyl acetate; soluble in dichloromethane; slightly soluble in ethanol and methanol; and insoluble in water. It has the empirical formula C30H32Cl3NO with a molecular weight of 528.9, and the following structural formula:
Anther Tablets are for oral administration. Each Anther Tablet contains 20 mg of Anther and 120 mg lumefantrine. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80.
Anther structural formula Lumefantrine structural formula
Anther Tablets, a fixed dose combination of Anther and lumefantrine in the ratio of 1:6, is an antimalarial agent .
Absorption
Following administration of Anther Tablets to healthy volunteers and patients with malaria, Anther is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for Anther, dihydroartemisinin (DHA), an active antimalarial metabolite of Anther, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of Anther Tablets in adult malaria patients are given in Table 4.
Study 2102 (n=50) | Study 2104 (n=48) | |
Anther | ||
Cmax (ng/mL) | 60.0 ± 32.5 | 83.8 ± 59.7 |
tmax (h) | 1.50 | 2.00 |
AUClast (ng·h/mL) | 146 ± 72.2 | 259 ± 150 |
t½ (h) | 1.6 ± 0.7 | 2.2 ± 1.9 |
DHA | ||
Cmax (ng/mL) | 104 ± 35.3 | 90.4 ± 48.9 |
tmax (h) | 1.76 | 2.00 |
AUClast (ng·h/mL) | 284 ± 83.8 | 285 ± 98.0 |
t½ (h) | 1.6 ± 0.6 | 2.2 ± 1.5 |
Lumefantrine | ||
Cmax (µg/mL) | 7.38 ± 3.19 | 9.80 ± 4.20 |
tmax (h) | 6.01 | 8.00 |
AUClast (µg·h/mL) | 158 ± 70.1 | 243 ± 117 |
t½ (h) | 101 ± 35.6 | 119 ± 51.0 |
aMean ± SD Cmax, AUClast, t½ and Median tmax
Food enhances the absorption of both Anther and lumefantrine. In healthy volunteers, the relative bioavailability of Anther was increased between 2- to 3-fold, and that of lumefantrine 16-fold when Anther Tablets were taken after a high-fat meal compared under fasted conditions. Patients should be encouraged to take Anther Tablets with a meal as soon as food can be tolerated .
Distribution
Anther 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% to 76%). Protein binding to human plasma proteins is linear.
Biotransformation
In human liver microsomes and recombinant CYP450 enzymes, the metabolism of Anther was catalyzed predominantly by CYP3A4/5. Dihydroartemisinin (DHA) is an active metabolite of Anther. The metabolism of Anther was also catalyzed to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. In vitro studies with Anther at therapeutic concentrations revealed no significant inhibition of the metabolic activities of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11. In vitro studies with Anther, DHA, and lumefantrine at therapeutic concentrations revealed no significant induction of the metabolic activities of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP3A5.
During repeated administration of Anther Tablets, systemic exposure of Anther decreased significantly, while concentrations of DHA increased, although not to a statistically significant degree. The artemether/DHA AUC ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. This suggests that there was induction of enzymes responsible for the metabolism of Anther.
In human liver microsomes and in recombinant CYP450 enzymes, lumefantrine was metabolized mainly by CYP3A4 to desbutyl-lumefantrine. The systemic exposure to the metabolite desbutyl-lumefantrine was less than 1% of the exposure to the parent compound. In vitro, lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.
Caution is recommended when combining Anther Tablets with substrates, inhibitors, or inducers of CYP3A4, especially antiretroviral drugs and those that prolong the QT interval (e.g., macrolide antibiotics, pimozide) [see Contraindications (4), Warnings and Precautions (5.1, 5.2, 5.3), and Drug Interactions (7)].
Coadministration of Anther Tablets with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and increase the risk of adverse reactions. In addition, many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Anther Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1, 5.4) and Drug Interactions (7.6)].
Elimination
Anther and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with an elimination half-life of 3 to 6 days in healthy volunteers and in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of Anther and lumefantrine.
In 16 healthy volunteers, neither lumefantrine nor Anther was found in the urine after administration of Anther Tablets, and urinary excretion of DHA amounted to less than 0.01% of the Anther dose.
Hepatic and Renal Impairment
No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. There is no significant renal excretion of lumefantrine, Anther and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended .
Pediatric Patients
The PK of Anther, DHA, and lumefantrine were obtained in 2 pediatric studies by sparse sampling using a population-based approach. PK estimates derived from a composite plasma concentration profile for Anther, DHA, and lumefantrine are provided in Table 4.
Systemic exposure to Anther, DHA, and lumefantrine, when dosed on a mg/kg body weight basis in pediatric patients (≥5 to <35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients.
Adults1 | Pediatric patients (body weight, kg) 2 | |||
Drug | 5 to <15 | 15 to <25 | 25 to <35 | |
Lumefantrine | ||||
Mean Cmax, range (mcg/mL) | 5.60 - 9.0 | 4.71 – 12.6 | Not Available | |
Mean AUClast, range (mcg·h/mL) | 410 - 561 | 372 – 699 | Not Available | |
Anther | ||||
Mean Cmax ± SD (ng/mL) | 186 ± 125 | 223 ± 309 | 198 ± 179 | 174 ± 145 |
Dihydroartemisinin | ||||
Mean Cmax ± SD (ng/mL) | 101 ± 58 | 54.7 ± 58.9 | 79.8 ± 80.5 | 65.3 ± 23.6 |
1 There are a total of 181 adults for lumefantrine pharmacokinetic parameters and a total of 25 adults for Anther and dihydroartemisinin pharmacokinetic parameters. 2 There are 477 children for the lumefantrine pharmacokinetic parameters; for Anther and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and 8 children for the 5 to <15, 15 to <25 and the 25 to <35 kg groups, respectively. |
Geriatric Patients
No specific pharmacokinetic studies have been performed in patients older than 65 years of age.
Drug Interactions
Rifampin (strong CYP3A4 inducer)
Oral administration of rifampin (600 mg daily), a strong CYP3A4 inducer, with Anther Tablets (6-dose regimen over 3 days) in 6 HIV-1 and tuberculosis co-infected adults without malaria resulted in significant decreases in exposure, in terms of AUC, to Anther, DHA and lumefantrine by 89%, 85% and 68%, respectively, when compared to exposure values after Anther Tablets alone. Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John’s wort is contraindicated with Anther Tablets .
Ketoconazole (potent CYP3A4 inhibitor)
Concurrent oral administration of ketoconazole (400 mg on day 1 followed by 200 mg on days 2, 3, 4 and 5) with Anther Tablets (single dose of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet) with a meal led to an increase in exposure, in terms of area under the curve (AUC), of Anther (2.3-fold), DHA (1.5-fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole was not evaluated. Based on this study, dose adjustment of Anther Tablets is considered unnecessary when administered with ketoconazole or other CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Anther Tablets should be used cautiously with other drugs that inhibit CYP3A4 (e.g., antiretroviral drugs, macrolide antibiotics, antidepressants, imidazole antifungal agents) .
Antimalarials
The oral administration of mefloquine in 14 healthy volunteers administered as 3 doses of 500 mg, 250 mg and 250 mg, followed 12 hours later by Anther Tablets (6 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet), had no effect on plasma concentrations of Anther or the artemether/DHA ratio. In the same study, there was a 30% reduction in Cmax and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production.
Intravenous administration of a single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of a 6-dose regimen of Anther Tablets had no effect on systemic exposure of DHA, lumefantrine or quinine in 14 healthy volunteers. Mean AUC of Anther were 46% lower when administered with quinine compared to Anther Tablets alone. This decrease in Anther exposure is not thought to be clinically significant. However, quinine should be used cautiously in patients following treatment with Anther Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval; ECG monitoring is advised if use of quinine is medically required .
Antiretroviral Drugs
The oral administration of lopinavir/ritonavir (400 mg/100 mg twice daily for 26 days) in 10 healthy volunteers coadministered with Anther Tablets (6-dose regimen over 3 days), resulted in a decrease in systemic exposures, in terms of AUC, to Anther and DHA by approximately 40%, but an increase in exposure to lumefantrine by approximately 2.3-fold. The oral administration of efavirenz (600 mg once daily for 26 days) in 12 healthy volunteers coadministered with Anther Tablets (6-dose regimen over 3 days), resulted in a decrease in exposures to Anther, DHA, and lumefantrine by approximately 50%, 45%, and 20%, respectively. Exposures to lopinavir/ritonavir and efavirenz were not significantly affected by concomitant use of Anther Tablets. Anther Tablets should be used cautiously in patients on antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors because decreased Anther, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Anther Tablets, and increased lumefantrine concentrations may cause QT prolongation [see Warnings and Precautions (5.3) and Drug Interactions (7.3)].
Hormonal Contraceptives
No clinical drug-drug interaction studies between Anther Tablets and hormonal contraceptives have been performed. In vitro studies revealed that the metabolism of ethinyl estradiol and levonorgestrel was not induced by Anther, DHA or lumefantrine. However, Anther has been reported to weakly induce, in humans, the activity of CYP2C19, CYP2B6, and CYP3A. Therefore, coadministration of Anther Tablets may potentially reduce the effectiveness of hormonal contraceptives [see Warnings and Precautions (5.3) and Drug Interactions (7.5)].
Mechanism of Action
Anther Tablets, a fixed ratio of 1:6 parts of Anther and lumefantrine, respectively, is an antimalarial agent. Anther is rapidly metabolized into an active metabolite dihydroartemisinin. The antimalarial activity of Anther and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine exerts its antimalarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of β-hematin by forming a complex with hemin. Both Anther and lumefantrine were shown to inhibit nucleic acid and protein synthesis.
Activity In Vitro and In Vivo
Anther and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum.
Drug Resistance
Strains of P. falciparum with a moderate decrease in susceptibility to Anther or lumefantrine alone can be selected in vitro or in vivo, but not maintained in the case of Anther. The clinical relevance of such an effect is not known.
In a healthy adult volunteer parallel-group study including a placebo and moxifloxacin control-group (n=42 per group), the administration of the 6-dose regimen of Anther Tablets was associated with prolongation of QTcF (Fridericia). Following administration of a 6-dose regimen of Anther Tablets consisting of 4 tablets per dose (total of 4 tablets of 80 mg artemether/480 mg lumefantrine) taken with food, the maximum mean change from baseline and placebo adjusted QTcF was 7.5 msec (1-sided 95% Upper CI: 11 msec). There was a concentration-dependent increase in QTcF for lumefantrine.
In clinical trials conducted in children, no patient had QTcF >500 msec. Over 5% of patients had an increase in QTcF of over 60 msec.
In clinical trials conducted in adults, QTcF prolongation of >500 msec was reported in 3 (0.3%) patients. Over 6% of adults had a QTcF increase of over 60 msec from baseline.
Carcinogenesis
Carcinogenicity studies were not conducted.
Mutagenesis
No evidence of mutagenicity was detected. The Anther: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo.
Impairment of Fertility
Pregnancy rates were reduced by about one-half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg. Male rats dosed for 70 days showed increases in abnormal sperm (87% abnormal) and increased testes weights at 30 mg/kg doses (about one-third the clinical dose). Higher doses (about 9 times the clinical dose) resulted in decreased sperm motility and 100% abnormal sperm cells.
Neonatal rats (7 to 21 days old) were more sensitive to the toxic effects of Anther (a component of Anther Tablets) than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.
The efficacy of Anther Tablets was evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum in HIV negative patients in 8 clinical studies. Uncomplicated malaria was defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/mcL to 200,000/mcL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children (≥5kg body weight) with uncomplicated malaria in China, Thailand, sub-Saharan Africa, Europe, and South America. Patients who had clinical features of severe malaria, severe cardiac, renal, or hepatic impairment were excluded.
The studies include two 4-dose studies assessing the efficacy of the components of the regimen, a study comparing a 4-dose versus a 6-dose regimen, and 5 additional 6-dose regimen studies.
Anther Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. Efficacy endpoints consisted of:
The modified intent to treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least 1 dose of study drug. Evaluable patients generally are all patients who had a day 7 and a day 28 parasitological assessment or experienced treatment failure by day 28.
Studies 1 and 2: The 2 studies which assessed the efficacy of Anther Tablets (4 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone were randomized, double-blind, comparative, single center, conducted in China. The efficacy results (Table 5) support that the combination of Anther and lumefantrine in Anther Tablets had a significantly higher 28-day cure rate compared to Anther and had a significantly faster parasite clearance time (PCT) and fever clearance time (FCT) compared to lumefantrine.
Study No. Region/patient ages | 28-day cure rate 2 n/N (%) patients | Median FCT 3 [25th,75th percentile] | Median PCT [25th,75th percentile] |
Study 1 China, ages 13 to 57 years | |||
Anther Tablets | 50/51 (98.0) | 24 hours [9, 48] | 30 hours [24, 36] |
Anther4 | 24/52 (46.2) | 21 hours [12, 30] | 30 hours [24, 33] |
Lumefantrine5 | 47/52 (90.4) | 60 hours [36, 78] | 54 hours [45, 66] |
Study 2 China, ages 12 to 65 years | |||
Anther Tablets | 50/52 (96.2) | 21 hours [6, 33] | 30 hours [24, 36] |
Lumefantrine 6 | 45/51 (88.2) | 36 hours [12, 60] | 48 hours [42, 60] |
1In mITT analysis, patients whose status was uncertain were classified as treatment failures. 2Efficacy cure rate based on blood smear microscopy. 3For patients who had a body temperature >37.5°C at baseline only 495% CI (Coartem Tablets – Anther) on 28-day cure rate: 37.8%, 66.0% 5P-value comparing Anther Tablets to lumefantrine on parasite clearance time (PCT) and fever clearance time (FCT): <0.001 6P-value comparing Anther Tablets to lumefantrine on parasite clearance time (PCT): <0.001 and on fever clearance time (FCT): <0.05 |
Results of 4-dose studies conducted in areas with high resistance such as Thailand during 1995-96 showed lower efficacy results than the above studies. Therefore, Study 3 was conducted.
Study 3: Study 3 was a randomized, double-blind, 2-center study conducted in Thailand in adults and children (aged ≥2 years), which compared the 4-dose regimen (administered over 48 hours) of Anther Tablets to a 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in mITT subjects was 81% (96/118) for the Anther Tablets 6-dose arm as compared to 71% (85/120) in the 4-dose arm.
Studies 4, 5, 6, 7, and 8: In these studies, Anther Tablets were administered as the 6-dose regimen.
In study 4, a total of 150 adults and children aged ≥2 years received Anther Tablets. In study 5, a total 164 adults and children ≥12 years received Anther Tablets. Both studies were conducted in Thailand.
Study 6 was a study of 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicated falciparum malaria when traveling in endemic regions.
Study 7 was conducted in Africa in 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillary temperature ≥37.5ºC.
Study 8 was conducted in Africa in 452 infants and children, aged 3 months to 12 years, weighing 5 kg to <35 kg, with fever (≥37.5°C axillary or ≥38°C rectally) or history of fever in the preceding 24 hours.
Results of 28-day cure rate, median parasite clearance time (PCT), and fever clearance time (FCT) for Studies 3 to 8 are reported in Table 6.
Study No. Region/ages | 28-day cure rate 1 n/N (%) patients | Median FCT 2 [25th, 75th percentile] | Median PCT [25th, 75th percentile] | |
mITT 3 | Evaluable | |||
Study 3 Thailand, ages 3 – 62 years | 96/118 (81.4) | 93/96 (96.9) | 35 hours [20, 46] | 44 hours [22, 47] |
Early failure4 | 0 | 0 | ||
Late failure5 | 4 (3.4) | 3 (3.1) | ||
Lost to follow-up | 18 (15.3) | |||
Other6 | 0 | |||
Study 4 Thailand, ages 2 – 63 years | 130/149 (87.2) | 130/134 (97.0) | 22 hours [19, 44] | NA |
Early failure4 | 0 | 0 | ||
Late failure5 | 4 (2.7) | 4 (3.0) | ||
Lost to follow-up | 13 (8.7) | |||
Other6 | 2 (1.3) | |||
Study 5 Thailand, ages 12 – 71 years | 148/164 (90.2) | 148/155 (95.5) | 29 hours [8, 51] | 29 hours [18, 40] |
Early failure4 | 0 | 0 | ||
Late failure5 | 7 (4.3) | 7 (4.5) | ||
Lost to follow-up | 9 (5.5) | |||
Other6 | 0 | |||
Study 6 Europe/Columbia, ages 16 – 66 years | 120/162 (74.1) | 119/124 (96.0) | 37 hours [18, 44] | 42 hours [34, 63] |
Early failure4 | 6 (3.7) | 1 (0.8) | ||
Late failure5 | 3 (1.9) | 3 (2.4) | ||
Lost to follow-up | 17 (10.5) | |||
Other6 | 16 (9.9) | 1 (0.8) | ||
Study 7 Africa, ages 2 months – 9 years | 268/310 (86.5) | 267/300 (89.0) | 8 hours [8, 24] | 24 hours [24, 36] |
Early failure4 | 2 (0.6) | 0 | ||
Late failure5 | 34 (11.0) | 33 (11.0) | ||
Lost to follow-up | 2 (0.6) | |||
Other6 | 4 (1.3) | |||
Study 8 Africa, ages 3 months – 12 years | 374/452 (82.7) | 370/419 (88.3) | 8 hours [8, 23] | 35 hours [24, 36] |
Early failure4 | 13 (2.9) | 0 | ||
Late failure5 | 49 (10.8) | 49 (11.7) | ||
Lost to follow-up | 6 (1.3) | |||
Other6 | 10 (2.2) | |||
1 Efficacy cure rate based on blood smear microscopy 2 For patients who had a body temperature >37.5°C at baseline only 3 In mITT analysis, patients whose status was uncertain were classified as treatment failures. 4 Early failures were usually defined as patients withdrawn for unsatisfactory therapeutic effect within the first 7 days or because they received another antimalarial medication within the first 7 days 5 Late failures were defined as patients achieving parasite clearance within 7 days but having parasite reappearance including recrudescence or new infection during the 28-day follow-up period 6 Other includes withdrawn due to protocol violation or non-compliance, received additional medication after day 7, withdrew consent, missing day 7 or 28 assessment |
In all studies, patients’ signs and symptoms of malaria resolved when parasites were cleared.
In studies conducted in areas with high transmission rates, such as Africa, reappearance of P. falciparum parasites may be due to recrudescence or a new infection.
The efficacy by body weight category for studies 7 and 8 is summarized in Table 7.
Study No. Age category | Anther Tablets 6-dose Regimen | ||
mITT population 1 | Evaluable population | ||
Median PCT [25 th ,75 th percentile] | 28-day cure rate 2 n/N (%) patients | 28-day cure rate 2 n/N (%) patients | |
Study 7 | |||
5 to <10 kg | 24 [24, 36] | 133/154 (86.4) | 133/149 (89.3) |
10 to <15 kg | 35 [24, 36] | 94/110 (85.5) | 94/107 (87.9) |
15 to 25 kg | 24 [24, 36] | 41/46 (89.1) | 40/44 (90.9) |
Study 8 3 | |||
5 to <10 kg | 36 [24, 36] | 61/83 (73.5) | 61/69 (88.4) |
10 to <15 kg | 35 [24, 36] | 160/190 (84.2) | 157/179 (87.7) |
15 to <25 kg | 35 [24, 36] | 123/145 (84.8) | 123/140 (87.9) |
25 to <35 kg | 26 [24, 36] | 30/34 (88.2) | 29/31 (93.5) |
1 In mITT analysis, patients whose status was uncertain were classified as treatment failures. 2 Efficacy cure rate based on blood smear microscopy 3 Anther Tablets administered as crushed tablets |
The efficacy of Anther Tablets for the treatment P. falciparum infections mixed with P. vivax was assessed in a small number of patients. Anther Tablets are only active against the erythrocytic phase of P. vivax malaria. Of the 43 patients with mixed infections at baseline, all cleared their parasitemia within 48 hours. However, parasite relapse occurred commonly (14/43; 33%). Relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoite forms that may remain dormant in the liver.
Anther (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).
Advise patients to read the FDA-Approved Patient Labeling.
Information for Safe Use
T2015-44
March 2015
FDA-Approved Patient Labeling
Patient Information
Anther®
(co-AR-tem)
(artemether and lumefantrine)
Tablets
Read this patient information before you start taking Anther. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is Anther?
Anther is a prescription medicine used to treat uncomplicated malaria in adults and children who weigh at least 11 pounds (5 kg).
Who should not take Anther?
Do not take Anther if you are allergic to any of the ingredients. See the end of this leaflet for a complete list of ingredients in Anther.
Do not take Anther if you are taking rifampin (medicine to treat leprosy or tuberculosis), certain medicines used to treat epilepsy (such as carbamazepine, phenytoin), or St. John’s wort (Hypericum perforatum, a medicinal plant or extract of this medicinal plant).
What should I tell my healthcare provider before taking Anther?
Before you take Anther, tell your healthcare provider about all your medical conditions including if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Anther and other medicines may affect each other causing side effects. Anther may affect the way other medicines work and other medicines may affect how Anther works.
Especially tell your doctor if you take:
Ask your healthcare provider if you are not sure if your medicine is 1 that is listed above. Know the medicines you take. Keep a list of your medicines with you to show your healthcare providers when you get a new medicine.
How should I take Anther?
Day 1: take 1 dose; 8 hours later take 1 dose
Day 2: take 1 dose in the morning, 1 dose in the evening
Day 3: take 1 dose in the morning, 1 dose in the evening
Take Anther for 3 days even if you are feeling better.
Tell your healthcare provider right away if:
What are the possible side effects of Anther?
Anther can cause serious side effects including:
The most common side effects in adults are:
The most common side effects in children are:
These are not all the possible side effects of Anther. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Anther?
Store Anther between 59ºF to 86ºF (15ºC to 30ºC).
Keep Anther and all medicines out of the reach of children.
General information about the safe and effective use of Anther.
Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use Anther for a condition for which it was not prescribed. Do not give Anther to other people, even if they have the same symptoms that you have. It may harm them.
This patient information leaflet summarizes the most important information about Anther. If you would like more information about Anther talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Anther that is written for health professionals. For more information call 1-855-262-7836.
What are the ingredients in Anther?
Active ingredients include: Anther, lumefantrine
Inactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polysorbate 80
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2015-45
March 2015
Depending on the reaction of the Anther after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Anther not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Anther addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology