1.NAME OF THE MEDICINAL PRODUCT
Piperaquine tetraphosphate and dihydroartemisinin film coated Tablets USP 320mg /40mg Taj Pharma.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains

piperaquine tetraphosphate USP      320 mg
(as the tetrahydrate; PQP)
artenimol (artenimol)                        40 mg
Excipients                                           q.s.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Film-coated tablet (tablet).
White oblong biconvex film-coated tablet (dimension 16x8mm / thickness 5.5mm) with a break-line
The tablet can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Piperaquine tetraphosphate and dihydroartemisinin tabletsis indicated for the treatment of uncomplicated Plasmodium falciparum malaria in adults, adolescents, children and infants 6 months and over and weighing 5 kg or more.

Consideration should be given to official guidance on the appropriate use of antimalarial medicinal products.

4.2  Posology and method of administration
Posology
Piperaquine tetraphosphate and dihydroartemisinin tablets should be administered over three consecutive days for a total of three doses taken at the same time each day.

Dosing should be based on body weight as shown in the table below.

Body weight (kg)Daily dose (mg)Tablet strength and number of tablets per dose
PQPArtenimol
5 to <78010½ x 160 mg / 20 mg tablet
7 to <13160201 x 160 mg / 20 mg tablet
13 to <24320401 x 320 mg / 40 mg tablet
24 to <36640802 x 320 mg / 40 mg tablets
36 to <759601203 x 320 mg / 40 mg tablets
75 to 1001,2801604 x 320 mg / 40 mg tablets
>100There are no data on which to base a dose recommendation in patients weighing >100 kg.

If a patient vomits within 30 minutes of taking Piperaquine tetraphosphate and dihydroartemisinin tablets, the whole dose should be re-administered; if a patient vomits within 30-60 minutes, half the dose should be re-administered. Re-dosing with Piperaquine tetraphosphate and dihydroartemisinin tablets should not be attempted more than once. If the second dose is vomited, alternative antimalarial therapy should be instituted.

If a dose is missed, it should be taken as soon as realised and then the recommended regimen continued until the full course of treatment has been completed.

There is no data on a second course of treatment.

No more than two courses of Piperaquine tetraphosphate and dihydroartemisinin tablets may be given within a 12 month period (see sections 4.4 and 5.3).

A second course of Piperaquine tetraphosphate and dihydroartemisinin tablets should not be given within 2 months after the first course due to the long elimination half-life of piperaquine (see sections 4.4 and 5.2).

Special populations

Elderly

Clinical studies of Piperaquine tetraphosphate and dihydroartemisinin tablets did not include patients aged 65 years and over, therefore no dosing recommendation can be made. Considering the possibility of age-associated decrease in hepatic and renal function, as well as a potential for heart disorders (see sections 4.3 and 4.4), caution should be exercised when administering the product to the elderly.

Hepatic and renal impairment

Piperaquine tetraphosphate and dihydroartemisinin tablets has not been evaluated in subjects with moderate or severe renal or hepatic insufficiency. Therefore, caution is advised when administering Piperaquine tetraphosphate and dihydroartemisinin tablets to these patients (see section 4.4).

Paediatric population

The safety and efficacy of Piperaquine tetraphosphate and dihydroartemisinin tablets in infants aged less than 6 months and in children weighing less than 5 kg has not been established. No data are available for these paediatric subsets.

Method of administration

Piperaquine tetraphosphate and dihydroartemisinin tablets should be taken orally with water and without food.

Each dose should be taken no less than 3 hours after the last food intake.

No food should be taken within 3 hours after each dose.

For patients unable to swallow the tablets, such as infants and young children, Piperaquine tetraphosphate and dihydroartemisinin tablets may be crushed and mixed with water. The mixture should be used immediately after preparation.

4.3 Contraindications
– Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

– Severe malaria according to WHO definition.

– Family history of sudden death or of congenital prolongation of the QTc interval.

– Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval.

– History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.

– Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

– Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.

– Taking medicinal products that are known to prolong the QTc interval. These include (but are not limited to):

  • Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol).
  • Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive medicinal products.
  • Certain antimicrobial medicinal products, including medicinal products of the following classes:

– macrolides (e.g. erythromycin, clarithromycin),

– fluoroquinolones (e.g. moxifloxacin, sparfloxacin),

– imidazole and triazole antifungalmedicinal products,

– and also pentamidine and saquinavir.

  • Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine).
  • Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.

– Recent treatment with medicinal products known to prolong the QTc interval that may still be circulating at the time that Piperaquine tetraphosphate and dihydroartemisinin tablets is commenced (e.g. mefloquine, halofantrine, lumefantrine, chloroquine, quinine and other antimalarial medicinal products) taking into account their elimination half-life.

4.4 Special Warnings and precautions for use
Piperaquine tetraphosphate and dihydroartemisinin tablets should not be used to treat severe falciparum malaria (see section 4.3) and, due to insufficient data, should not be used to treat malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale.

The long half-life of piperaquine (about 22 days) should be kept in mind in the event that another anti-malarial agent is started due to treatment failure or a new malaria infection (see below and sections 4.3 and 4.5).

Piperaquine is a mild inhibitor of CYP3A4. Caution is recommended when co-administering Piperaquine tetraphosphate and dihydroartemisinin tablets with medicinal products exhibiting variable patterns of inhibition, induction or competition for CYP3A4 as the therapeutic and/or toxic effects of some co-administered medicinal products could be altered.

Piperaquine is also a substrate of CYP3A4. A moderate increase of piperaquine plasma concentrations (<2-fold) was observed when co-administered with strong CYP3A4 inhibitors, resulting in a potential exacerbation of the effect on QTc prolongation (see section 4.5).

Exposure to piperaquine may also be increased when co-administered with mild or moderate CYP3A4-inhibitors (e.g. oral contraceptives). Therefore, caution should be applied when co-administering Piperaquine tetraphosphate and dihydroartemisinin tablets with any CYP3A4-inhibitor and ECG monitoring should be considered.

Due to the lack of multiple dose PK data for piperaquine, administration of any strong CYP3A4-inhibitors should be discouraged after initiation (i.e. the first dose) of Piperaquine tetraphosphate and dihydroartemisinin tablets (see sections 4.5 and 5.2).

Piperaquine tetraphosphate and dihydroartemisinin tablets should not be used during pregnancy in situations where other suitable and effective antimalarials are available (see section 4.6).

In the absence of carcinogenicity study data, and due to lack of clinical experience with repeated courses of treatment in humans, no more than two courses of Piperaquine tetraphosphate and dihydroartemisinin tablets should be given in a 12-month period (see sections 4.2 and 5.3).

Effects on cardiac repolarization

In clinical trials with Piperaquine tetraphosphate and dihydroartemisinin tablets limited ECGs were obtained during treatment. These showed that QTc prolongation occurred more frequently and to a larger extent in association with Piperaquine tetraphosphate and dihydroartemisinin tablets therapy than with the comparators (see section 5.1 for details of the comparators). Analysis of cardiac adverse events in clinical trials showed that these were reported more frequently in Piperaquine tetraphosphate and dihydroartemisinin tablets treated patients than in those treated with comparator antimalarial (see section 4.8). Before the third dose of Piperaquine tetraphosphate and dihydroartemisinin tablets, in one of the two Phase III studies 3/767 patients (0.4%) were reported to have a QTcF value of >500 ms versus none in the comparator group.

The potential for Piperaquine tetraphosphate and dihydroartemisinin tablets to prolong the QTc interval was investigated in parallel groups of healthy volunteers who took each dose with high (~1000 Kcal) or low (~400 Kcal) fat/calorie meals or in fasting conditions. Compared to placebo, the maximum mean increases in QTcF on Day 3 of dosing with Piperaquine tetraphosphate and dihydroartemisinin tablets were 45.2, 35.5 and 21.0 msec under respective dosing conditions. The QTcF prolongation observed under fasting conditions lasted between 4 and 11 hours after the last dose was administered on Day 3. The mean QTcF prolongation compared to placebo decreased to 11.8 msec at 24 hours and to 7.5 msec at 48 hours. No healthy subject dosed in fasting conditions showed a QTcF greater than 480 msec or an increase over baseline greater than 60 msec. The number of subjects with QTcF greater than 480 msec after dosing with low fat meals was 3/64, while 10/64 had QTcF values over this threshold after dosing with high fat meals. No subject had a QTcF value greater than 500 msec in any of the dosing conditions.

An ECG should be obtained as early as possible during treatment with Piperaquine tetraphosphate and dihydroartemisinin tablets and ECG monitoring should be applied in patients who may have a higher risk of developing arrhythmia in association with QTc prolongation (see below).

When clinically appropriate, consideration should be given to obtaining an ECG from all patients before the last of the three daily doses is taken and approximately 4-6 hours after the last dose, since the risk of QTc interval prolongation may be greatest during this period (see section 5.2). QTc intervals of more than 500 ms are associated with a pronounced risk for potentially life-threatening ventricular tachyarrhythmias. Therefore, ECG monitoring during the following 24-48 hours should be applied for patients found to have a prolongation to this extent. These patients should not receive another dose of Piperaquine tetraphosphate and dihydroartemisinin tablets and alternative antimalarial therapy should be instituted.

Compared to adult males, female patients and elderly patients have longer QTc intervals. Therefore, they may be more sensitive to the effects of QTc-prolonging medications such as Piperaquine tetraphosphate and dihydroartemisinin tablets so that special caution is required.

Paediatric population

Special precaution is advised in young children when vomiting, as they are likely to develop electrolyte disturbances. These may increase the QTc-prolonging effect of Piperaquine tetraphosphate and dihydroartemisinin tablets (see section 4.3).

Hepatic and renal impairment

Piperaquine tetraphosphate and dihydroartemisinin tablets has not been evaluated in patients with moderate or severe renal or hepatic insufficiency (see section 4.2). Due to the potential for higher plasma concentrations of piperaquine to occur, caution is advised if Piperaquine tetraphosphate and dihydroartemisinin tablets is administered to patients with jaundice and/or with moderate or severe renal or hepatic insufficiency, and ECG and blood potassium monitoring are advised.

 4.5 Interaction with other medicinal products and other forms of interaction
Piperaquine tetraphosphate and dihydroartemisinin tablets is contraindicated in patients already taking other medicinal products that are known to prolong the QTc interval due to the risk of a pharmacodynamic interaction leading to an additive effect on the QTc interval (see sections 4.3 and 4.4).

A limited number of drug-drug pharmacokinetic interaction studies with Piperaquine tetraphosphate and dihydroartemisinin tablets have been performed in healthy adult subjects. Therefore the assessment of the potential for drug-drug interactions to occur is based on either in vivo or in vitro studies.

Effect of Piperaquine tetraphosphate and dihydroartemisinin tablets on co-administered medicinal products

Piperaquine is metabolised by, and is an inhibitor of CYP3A4. The concurrent administration of oral Piperaquine tetraphosphate and dihydroartemisinin tablets with 7.5 mg oral midazolam, a CYP3A4 probe substrate, led to a modest increase (≤2-fold) in midazolam and its metabolites exposures in healthy adult subjects. This inhibitory effect was no longer evident one week after last administration of Piperaquine tetraphosphate and dihydroartemisinin tablets. Therefore, particular attention should be paid when medicinal products that have a narrow therapeutic index (e.g. antiretroviral medicinal products and cyclosporine) are co-administered with Piperaquine tetraphosphate and dihydroartemisinin tablets.

From in vitro data, piperaquine undergoes a low level of metabolism by CYP2C19, and is also an inhibitor of this enzyme. There is the potential for reducing the rate of metabolism of other substrates of this enzyme, such as omeprazole, with consequent increase of their plasma concentration, and therefore, of their toxicity.

Piperaquine has the potential to increase the rate of metabolism for CYP2E1 substrates resulting in a decrease in the plasma concentrations of substrates such as paracetamol or theophylline, and the anaesthetic gases enflurane, halothane and isoflurane. The main consequence of this interaction could be a reduction of efficacy of the co-administered medicinal products.

Artenimol administration may result in a slight decrease in CYP1A2 activity. Caution is therefore, advised when Piperaquine tetraphosphate and dihydroartemisinin tablets is administered concomitantly with medicinal products metabolised by this enzyme that have a narrow therapeutic index, such as theophylline. Any effects are unlikely to persist beyond 24 hours after the last intake of artenimol.

Effect of co-administered medicinal products on Piperaquine tetraphosphate and dihydroartemisinin tablets

Piperaquine is metabolised by CYP3A4 in vitro. The concurrent administration of a single dose of oral clarithromycin, (a strong CYP3A4 inhibitor probe) with a single dose of oral Piperaquine tetraphosphate and dihydroartemisinin tablets led to a modest increase (≤2-fold) in piperaquine exposure in healthy adult subjects. This increase in exposure to the antimalarial combination may result in an exacerbation of the effect on QTc (see section 4.4). Therefore, particular caution is required if Piperaquine tetraphosphate and dihydroartemisinin tablets is administered to patients taking potent CYP3A4 inhibitors (e.g. some protease inhibitors [amprenavir, atazanavir, indinavir, nelfinavir, ritonavir], nefazodone or verapamil), and ECG monitoring should be considered due to the risk of higher plasma concentrations of piperaquine (see section 4.4).

Enzyme inducing medicinal products such as rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort (Hypericum perforatum) are likely to lead to reduced piperaquine plasma concentrations. The concentration of artenimol may also be reduced. Concomitant treatment with such medicinal products is not recommended.

Paediatric population

Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Oral contraceptives

When co-administered to healthy women, Piperaquine tetraphosphate and dihydroartemisinin tablets exerted only a minimum effect on an estrogen/progestinic combination oral contraceptive treatment increasing the ethynilestradiol rate of absorption (expressed by geometric mean Cmax) of about 28% but not significantly changing the exposure to ethynilestradiol and levonorgestrel and not influencing contraception activity as demonstrated by the similar plasma concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and progesterone observed after oral contraceptive treatment with or without concomitant Piperaquine tetraphosphate and dihydroartemisinin tablets administration.

Food interaction

Absorption of piperaquine is increased in the presence of fatty food (see sections 4.4 and 5.2) which may increase its effect on QTc interval. Therefore, Piperaquine tetraphosphate and dihydroartemisinin tablets should be taken with water only as described in section 4.2. Piperaquine tetraphosphate and dihydroartemisinin tablets should not be taken with grapefruit juice as it is likely to lead to increased piperaquine plasma concentrations.

 4.6 Fertility, Pregnancy and lactation
Pregnancy

There are insufficient data on the use of artenimol and piperaquine in pregnant women. Based on animal data, Piperaquine tetraphosphate and dihydroartemisinin tablets is suspected to cause serious birth defects when administered during the first trimester of pregnancy (see sections 4.4 and 5.3). Reproductive studies with artemisinin derivatives have demonstrated teratogenic potential with an increased risk during early gestation (see section 5.3). Piperaquine was not teratogenic in the rat or rabbit. In perinatal and postnatal studies in rats, piperaquine was associated with delivery complications. However, there was no delay in neonatal development following exposure in utero or via milk.

Piperaquine tetraphosphate and dihydroartemisinin tablets should not be used during pregnancy in situations where other suitable and effective anti-malarials are available (see section 4.4).

Breast-feeding

Animal data suggest excretion of piperaquine into breast milk but no data are available in humans. Women taking Piperaquine tetraphosphate and dihydroartemisinin tablets should not breast-feed during their treatment.

Fertility

There are no specific data relating to the effects of piperaquine on fertility, however, to date no adverse events have been reported during clinical use. Moreover, data obtained in animal studies show that fertility is unaffected by artenimol in both females and males.

 4.7 Effects on ability to drive and use machines
Adverse event data collected in clinical trials suggest that Piperaquine tetraphosphate and dihydroartemisinin tablets has no influence on the ability to drive and operate machines once the patient has recovered from the acute infection.

4.8 Undesirable Effects
Summary of the safety profile

The safety of Piperaquine tetraphosphate and dihydroartemisinin tablets has been evaluated in two phase III open-label studies involving 1,239 paediatric patients up to 18 years and 566 adult patients >18 years treated with Piperaquine tetraphosphate and dihydroartemisinin tablets.

In a randomized trial in which 767 adults and children with uncomplicated P. falciparum malaria were exposed to Piperaquine tetraphosphate and dihydroartemisinin tablets, 25% of subjects were judged to have experienced an adverse drug reaction (ADR). No single type of ADR occurred at an incidence of ≥5%. The most frequent ADRs observed at an incidence ≥1.0% were: Headache (3.9%), Electrocardiogram QTc Prolonged (3.4%), Pfalciparum infection (3.0%), Anaemia (2.8%), Eosinophilia (1.7%), Haemoglobin decreased (1.7%), Sinus tachycardia (1.7%), Asthenia (1.6%), Haematocrit [decreased] (1.6%), Pyrexia (1.5%), Red Blood Cell Count decreased (1.4%). A total of 6 (0.8%) subjects had serious ADRs in the study.

In a second randomized trial, 1,038 children, aged between 6 months and 5 years, were exposed to Piperaquine tetraphosphate and dihydroartemisinin tablets and 71% were judged to have experienced an ADR. The following ADRs were observed at an incidence of ≥5.0%: Cough (32%), Pyrexia (22.4%), Influenza (16.0%), P. falciparum infection (14.1%), Diarrhoea (9.4%), Vomiting (5.5%) and Anorexia (5.2%). A total of 15 (1.5%) subjects had serious ADRs in the study.

Tabulated list of adverse reactions

In the tables below, ADRs are listed under system organ class (SOC), and ranked by headings of frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness, using the following 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 the available data). The table in this section is for adult patients only. A corresponding table for paediatric patients is presented in the specific section below.

Frequency of ADRs in adult patients participating in clinical studies with Piperaquine tetraphosphate and dihydroartemisinin tablets:

SOCVery CommonCommonUncommon
Infections and infestationsP falciparum infectionRespiratory tract infection

Influenza

Blood and lymphatic system disordersAnaemia
Metabolism and nutrition disordersAnorexia
Nervous system disordersHeadacheConvulsion

Dizziness

Cardiac disordersQTc prolonged

Tachycardia

Cardiac conduction disorders

Sinus arrhythmias

Bradycardia

Respiratory, thoracic and mediastinal disordersCough
Gastrointestinal disordersVomiting

Diarrhoea

Nausea

Abdominal pain

Hepatobiliary disordersHepatitis

Hepatomegaly

Abnormal liver function tests

Skin and subcutaneous Tissue disordersPruritis
Musculoskeletal and connective tissue disordersArthralgia

Myalgia

General disorders and administration site conditionsAsthenia

Pyrexia

Description of selected adverse reactions

The ADRs noted for Piperaquine tetraphosphate and dihydroartemisinin tablets were generally mild in severity, and the majority were non-serious. Reactions such as cough, pyrexia, headache, Pfalciparum infection, anaemia, asthenia, anorexia and the observed changes in blood cell parameters are consistent with those expected in patients with acute malaria. The effect on prolongation of the QTc interval was observed on Day 2, and had resolved by Day 7 (the next time point at which ECGs were performed).

Paediatric population

A tabular overview of the frequency of the ADRs in paediatric patients is given below. The majority of paediatric experience is derived from African children aged 6 months to 5 years.

Frequency of ADRs in paediatric patients participating in clinical studies with Piperaquine tetraphosphate and dihydroartemisinin tablets:

SOCVery CommonCommonUncommon
Infections and infestationsInfluenza

P. falciparum infection

Respiratory tract infection

Ear infection

Blood and lymphatic system disordersThrombocytopenia

Leukopenias/neutropenia

Leuckocytoses NEC

Anaemia

Thrombocythaemia

Splenomegaly

Lymphadenopathy

Hypochromasia

Metabolism and nutrition disordersAnorexia
Nervous system disordersConvulsion

Headache

Eye disordersConjunctivitis
Cardiac disordersQT/QTc prolonged

Heart rate irregular

Cardiac conduction disorders

Cardiac murmur

Respiratory, thoracic and mediastinal disordersCoughRhinorrhoea

Epistaxis

Gastrointestinal disordersVomiting

Diarrhoea

Abdominal pain

Stomatitis

Nausea

Hepatobiliary disordersHepatitis

Hepatomegaly

Abnormal liver function tests

Jaundice

Skin and subcutaneous Tissue disordersDermatitis

Rash

Acanthosis

Pruritis

Musculoskeletal and connective tissue disordersArthralgia
General disorders and administration site conditionsPyrexiaAsthenia

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
In clinical trials, nine patients received double the cumulative intended dose of Piperaquine tetraphosphate and dihydroartemisinin tablets. The safety profile of these patients did not differ from that of patients receiving the recommended dose, with no patient reporting SAEs.

In cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate, including ECG monitoring because of the possibility of QTc interval prolongation (see section 4.4)

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiprotozoals, antimalarials, artemisinin and derivatives, combinations.

Pharmacodynamic effects
Artenimol is able to reach high concentrations within the parasitized erythrocytes. Its endoperoxide bridge is thought to be essential for its antimalarial activity, causing free-radical damage to parasite membrane systems including:

  • Inhibition of falciparum sarcoplasmic-endoplasmic reticulum calcium ATPase,
  • Interference with mitochondrial electron transport
  • Interference with parasite transport proteins
  • Disruption of parasite mitochondrial function

The exact mechanism of action of piperaquine is unknown, but it likely mirrors that of chloroquine, a close structural analogue. Chloroquine binds to toxic haeme (derived from the patient’s haemoglobin) within the malaria parasite, preventing its detoxification via a polymerisation step. Piperaquine is a bisquinoline, and this class has shown good antimalarial activity against chloroquine-resistant Plasmodium strains in vitro. The bulky bisquinolone structure may be important for activity against chloroquine- resistant strains, and may act through the following mechanisms:

  • Inhibition of the transporters that efflux chloroquine from the parasite food vacuole
  • Inhibition of haem-digestion pathway in the parasite food vacuole.

Resistance to piperaquine (when used as monotherapy) has been reported.

The efficacy and safety of Piperaquine tetraphosphate and dihydroartemisinin tablets have been assessed in two large randomised, open-label clinical trials:

Study DM040010 was conducted in Asian adult and paediatric patients with uncomplicated P. falciparum malaria. Piperaquine tetraphosphate and dihydroartemisinin tablets treatment was compared with Artesunate + Mefloquine (AS + MQ). The primary end-point was the PCR-corrected cure rate at Day 63.

Study DM040011 was conducted in African paediatric patients with uncomplicated P. falciparum malaria. Piperaquine tetraphosphate and dihydroartemisinin tablets treatment was compared with Artemether + Lumefantrine (A + L). The primary end-point was PCR-corrected cure rate at Day 28.

The results for the primary endpoint in the modified intent to treat (m-ITT) populations (defined as all randomised patients who received at least one dose of the study treatment, with the exclusion of those patients lost to follow up for unknown reasons) were as follows:

StudyPCR-corrected cure rate (m-ITT)
Piperaquine tetraphosphate and dihydroartemisinin tabletsAS + MQA + L95 % two-sided CI on the treatment difference (Piperaquine tetraphosphate and dihydroartemisinin tablets – Comparator); p-value
DM040010 (n=1087)97.0%95.3%(-0.84, 4.19)%; p=0.161
DM040011 (n=1524)92.7%94.8%(-4.59, 0.45)%; p=0.128

In each case the results confirmed that Piperaquine tetraphosphate and dihydroartemisinin tablets was not inferior to the comparator medicinal product. In both studies, the true treatment failure rate was below the 5% efficacy threshold set by WHO.

The age-specific PCR-corrected cure rates in the m-ITT populations are tabulated below for the Asian and African studies, respectively:

StudyPCR-corrected cure rate (m-ITT)
Piperaquine tetraphosphate and dihydroartemisinin tabletsAS + MQA + L95% two-sided CI on the treatment difference (Piperaquine tetraphosphate and dihydroartemisinin tablets – Comparator); p-value
DM04010 (n=1087)

≤5years

>5 to ≤12years

>12 to ≤18 years

>18 to ≤64 years

100.0%

98.2%

97.3%

96.6%

100.0%

96.5%

100.0%

94.4%

(-3.67, 7.09)%; 0.605

(-6.40, 0.99)%; 1.000

(-0.98, 5.30)%; 0.146

DM04011 (n=1524)

≤1 year

>1 to ≤ 2 years

>2 to ≤5 years

91.5%

92.6%

93.0%

98.5%

94.6%

94.0%

(-12.66, -1.32)%(1); 0.064

(-6.76, 2.63)%; 0.413

(-4.41, 2.47)%; 0.590

(1) This CI is asymptotic because the exact CI could not be computed

5.2 Pharmacokinetic properties
Pharmacokinetic profiles of artenimol and piperaquine have been investigated in animal models and in different human populations (healthy volunteers, adult patients and paediatric patients).

Absorption

Artenimol is very rapidly absorbed, Tmax being approximately 1-2 hrs after single and multiple dosing. In patients, mean Cmax (CV%) and AUCINF of artenimol (observed after the first dose of Piperaquine tetraphosphate and dihydroartemisinin tablets) were 752 (47%) ng/ml and 2,002 (45 %) ng/ml*h, respectively.

Artenimol bioavailability appears to be higher in malaria patients than in healthy volunteers, possibly because malaria per se has an effect on artenimol disposition. This may reflect malaria-associated impairment of hepatic function, causing an increase in artenimol bioavailability (reduction of first hepatic effect) without affecting its apparent elimination half-life, which is absorption rate limited. In healthy male volunteers under fasting conditions, mean Cmax and AUCINF of artenimol ranged between 180-252 ng/ml and 516-684 ng/ml*h, respectively.

The systemic exposure to artenimol was slightly lower following the last dose of Piperaquine tetraphosphate and dihydroartemisinin tablets (lower than after the first dose by up to 15%). artenimol pharmacokinetic parameters were found to be similar in healthy volunteers of Asian and Caucasian origin. artenimol systemic exposure on the last day of treatment was higher in females than in males, the difference being within 30%.

In healthy volunteers, artenimol exposure was increased by 43% when administered with a high fat/high calorie meal.

Piperaquine, a highly lipophilic compound, is slowly absorbed. In humans, piperaquine has a Tmax of approximately 5 hours following a single and repeated dose. In patients mean (CV%) Cmax and AUC0-24 (observed after the first dose of Piperaquine tetraphosphate and dihydroartemisinin tablets) were 179 (62%) ng/ml and 1,679 (47%) ng/ml*h, respectively. Due to its slow elimination, piperaquine accumulates in plasma after multiple doses with an accumulation factor of approximately 3. Piperaquine pharmacokinetic parameters were found to be similar in healthy volunteers of Asian and Caucasian origin. On the other hand, on the last day of Eurtartesim treatment, the piperaquine maximum plasma concentration was higher in female than in male healthy volunteers, the difference being in the order of 30 to 50%.

In healthy volunteers, piperaquine exposure is increased approximately 3-fold when administered with a high fat/high calorie meal. This pharmacokinetic effect is accompanied by an increased effect on prolongation of the QT interval. Accordingly, Piperaquine tetraphosphate and dihydroartemisinin tablets should be administered with water no less than 3 hours after the last food intake, and no food should be taken within 3 hours after each dose (see section 4.2).

Distribution

Both piperaquine and artenimol are highly bound to human plasma proteins: the protein binding observed in in vitro studies was 44-93% for artenimol and >99% for piperaquine. Moreover, from in vitro and in vivo data in animals, piperaquine and artenimol tend to accumulate in RBC.

Artenimol was observed to have a small volume of distribution in humans (0.8 l/kg; CV 35.5%). Pharmacokinetic parameters observed for piperaquine in humans indicate that this active substance has a large volume of distribution (730 l/kg; CV 37.5%).

Biotransformation

Artenimol is principally converted to α- artenimol-β-glucuronide (α- artenimol-G). Studies in human liver microsomes showed that artenimol was metabolised by the UDP-glucuronosyltransferase (UGT1A9 and UGT2B7) to α- artenimol-G with no cytochrome P450-mediated metabolism.

In vitro drug-drug interaction studies revealed that artenimol is an inhibitor of CYP1A2; therefore, there is the potential for artenimol to increase plasma concentrations of CYP1A2 substrates (see section 4.5).

In vitro metabolism studies demonstrated that piperaquine is metabolised by human hepatocytes (approximately 85% of piperaquine remained after 2 hours incubation at 37°C). Piperaquine was mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Piperaquine was found to be an inhibitor of CYP3A4 (also in a time-dependent way) and to a lesser extent of CYP2C19, while it stimulated the activity of CYP2E1.

No effect on the metabolite profile of piperaquine in human hepatocytes was observed when piperaquine was co-incubated withartenimol. The piperaquine major metabolites were a carboxyl acid cleavage product, and a mono-N-oxidated product.

In human studies, piperaquine was found to be a mild inhibitor of CYP3A4 enzyme while potent inhibitors of CYP3A4 activity caused mild inhibition of piperaquine metabolism (see section 4.5).

Elimination

The elimination half-life of artenimol is approximately 1 hour. The mean oral clearance for adult patients with malaria was 1.34 l/h/kg. The mean oral clearance was slightly higher for paediatric patients, however the differences were minor in magnitude (<20%). Artenimol is eliminated by metabolism (mainly glucuroconjugation). Its clearance was found to be slightly lower in female than in male healthy volunteers. Data regarding artenimol excretion in humans are scarce. However, it is reported in the literature that the excretion of unchanged active substance in human urine and faeces is negligible for artemisinin derivatives.

The elimination half-life of piperaquine is around 22 days for adult patients and around 20 days for paediatric patients. The mean oral clearance for adult patients with malaria was 2.09 l/h/kg, while in paediatric patients was 2.43 l/h/kg. Due to its long elimination half-life, piperaquine accumulates after multiple dosing.

Animal studies showed that radiolabelled piperaquine is excreted by the biliary route, while urinary excretion is negligible.

Pharmacokinetics in special patient populations

No specific pharmacokinetic studies have been performed in patients with hepatic or renal insufficiency, or in elderly people.

In a paediatric pharmacokinetic study, and based on very limited sampling, minor differences were observed for artenimol pharmacokinetics between the paediatric and adult populations. The mean clearance (1.45 l/h/kg) was slightly faster in the paediatric patients than in the adult patients (1.34 l/h/kg), while the mean volume of distribution in the paediatric patients (0.705 l/kg) was lower than in the adults (0.801 l/kg).

The same comparison showed that piperaquine absorption rate constant and terminal half-life in children were predominantly similar to those seen in adults. However, the apparent clearance was faster (1.30 versus 1.14 l/h/kg) and the apparent total volume of distribution was lower in the paediatric population (623 versus 730 l/kg).

 5.3 Preclinical safety data
General toxicity

Literature data concerning chronic toxicity of piperaquine in dogs and monkeys indicate some hepatotoxicity and mild reversible depression of total white cell and neutrophil counts.

The most important nonclinical safety findings after repeated dosing were the infiltration of macrophages with intracytoplasmic basophilic granular material consistent with phospholipidosis and degenerative lesions in numerous organs and tissues. These adverse reactions were seen in animals at exposure levels similar to clinical exposure levels, and with possible relevance to clinical use. It is not known whether these toxic effects are reversible.

Artenimol and piperaquine were not genotoxic/clastogenic based on in vitro and in vivo testing.

No carcinogenicity studies have been performed.

Artenimol causes embryolethality and teratogenicity in rats and rabbits.

Piperaquine did not induce malformation in rats and rabbits. In a perinatal and postnatal development study (segment III) in female rats treated with 80 mg/kg, some animals had a delay of delivery inducing mortality of the neonates. In females delivering normally the development, behaviour and growth of the surviving progeny was normal following exposure in utero or via milk. No reproduction toxicity studies have been performed with the combination of artenimol and piperaquine.

Central nervous system (CNS) toxicity

There is potential for neurotoxicity of artemisinin derivatives in man and animals, which is strongly related to the dose, route and formulations of the different artenimol pro-drugs. In humans, the potential neurotoxicity of orally administered artenimol can be considered highly unlikely, given the rapid clearance ofartenimol, and its short exposure (3 days of treatment for malaria patients). There was no evidence of artenimol-induced lesions in the specific nuclei in rats or dogs, even at lethal dose.

Cardiovascular toxicity

Effects on blood pressure and on PR and QRS duration were observed at high piperaquine doses. The most important potential cardiac effect was related to cardiac conduction.

In the hERG test, the IC50 was 0.15 µmol for piperaquine and 7.7 µmol forartenimol. The association of artenimol and piperaquine does not produce hERG inhibition greater than that of the single compounds.

Phototoxicity

There are no phototoxicity concerns withartenimol, as it does not absorb in the range of 290-700 nm.

Piperaquine has an absorption maximum at 352 nm. Since piperaquine is present in the skin (about 9% in the non-pigmented rat and only 3% in the pigmented rat), slight phototoxic reactions (swelling and erythema) were observed 24 hours after oral treatment in mice exposed to UV radiation.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Tablet core
Pre-gelatinised starch
Dextrin
Hypromellose (E464)
Croscarmellose sodium
Magnesium stearate (E572)

Film coating
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400

6.2 Incompatibilities
Not applicable.

6.3  Shelf life
2 years.

6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container
Piperaquine tetraphosphate and dihydroartemisinin tablets tablets are packaged in PVC/PVDC/aluminium blisters containing 3, 6, 9 or 12 tablets.

6.6 Special precautions for disposal and other handling
No special requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Piperaquine tetraphosphate 320mg and Dihydroartemisinin 40mg film coated Tablets USP Taj Pharma

Package leaflet: Information for the patient

Piperaquine tetraphosphate and dihydroartemisinin film coated Tablets USP 320mg /40mg Taj Pharma.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Piperaquine tetraphosphate and dihydroartemisinin Tablets is and what it is used for
2. Before you are given Piperaquine tetraphosphate and dihydroartemisinin Tablets
3. How you will be given  Piperaquine tetraphosphate and dihydroartemisinin Tablets
4. Possible side effects
5. How Piperaquine tetraphosphate and dihydroartemisinin Tablets is stored
6. Further Information

1. What Piperaquine tetraphosphate and dihydroartemisinin Tablets is and what it is used for
Piperaquine tetraphosphate and dihydroartemisinin Tablets contains the ingredients piperaquine tetraphosphate and dihydroartemisinin. It is used to treat uncomplicated malaria when use of a medicine given by mouth is appropriate.

Malaria is caused by infection with a parasite called Plasmodium, spread by the bite of an infected mosquito.There are different types of Plasmodium parasite. Piperaquine tetraphosphate and dihydroartemisinin Tablets kills the Plasmodium falciparum parasite.

The medicine can be taken by adults, children and infants over 6 months old who weigh 5 kilograms or more.

2. Before you are given Piperaquine tetraphosphate and dihydroartemisinin Tablets
Do not take Piperaquine tetraphosphate and dihydroartemisinin Tablets if you or your child:
• is allergic (hypersensitive) to the active substances, piperaquine tetraphosphate or dihydroartemisinin, or to any of the other ingredients of Piperaquine tetraphosphate and dihydroartemisinin Tablets (see section 6 for a list of these);
• has a severe type of malaria infection which has affected parts of your body such as the brain, lungs or kidneys;
• has a heart condition, such as changes to the rhythm or rate of your heart beat, or heart disease;
• knows that any member of your family (parents, grandparents, brothers or sisters) died suddenly due to a heart problem or was born with heart problems;
• suffers from changes to the levels of salts in your body (electrolyte imbalances);
• is taking other medicines that can have an effect on heart rhythm, such as:
– quinidine, disopyramide, procainamide, amiodarone, dofetilide, ibutilide, hydroquinidine or sotalol;
– medicines used to treat depression;
– medicines used to treat mental health problems such as phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine;
– medicines used to treat infections. These include some of the types of medicines used to treat bacterial infections (macrolides [such as erythromycin or clarithromycin] and fluoroquinolones [such as moxifloxacin and sparfloxacin]) or fungal infections (including fluconazole and imidazole) as well as pentamidine (used to treat a specific type of pneumonia) and saquinavir (for treatment of HIV);
– antihistamines used to treat allergies or inflammation such as terfenadine, astemizole or mizolastine;
– certain medicines used to treat stomach problems such as cisapride, domperidone or droperidol;
– other medicines such as vinca alkaloids and arsenic trioxide (used to treat certain cancers), bepridil (used to treat angina), diphemanil (used to treat stomach disturbances), levomethadyl and methadone (used to treat drug addiction), and probucol (used to treat high blood cholesterol levels).
• has recently (for example within about one month) been treated for malaria with certain medicines or has taken certain medicines to prevent malaria. These medicines include: mefloquine, halofantrine, lumefantrine, chloroquine or quinine

If any of the above applies to you or your child or if you are unsure, tell your doctor or pharmacist before taking or giving Piperaquine tetraphosphate and dihydroartemisinin Tablets.

Take special care with Piperaquine tetraphosphate and dihydroartemisinin Tablets
Check with your doctor or pharmacist before taking this medicine if you or your child:
• has liver or kidney problems;
• has a malaria infection caused by a parasite other than Plasmodium falciparum;
• is taking or has taken any other medicines for the treatment of malaria (other than those mentioned above);
• is pregnant or breastfeeding (see below);
• is female, elderly (over 65 years) or vomiting;
• is taking certain other medicines which could cause possible metabolic interactions. Examples are listed in the section “Taking other medicines”.

If you are not sure about any of the above, please ask your doctor or pharmacist.

Use in children
Do not give this medicine to infants under 6 months or below 5 kg in weight.

Taking other medicines
Please tell your doctor or pharmacist if you or your child is taking or has recently taken any other medicines, including medicines obtained without a prescription. Some medicines can affect the way Piperaquine tetraphosphate and dihydroartemisinin Tablets works and your doctor may decide that Piperaquine tetraphosphate and dihydroartemisinin Tablets is not suitable or that extra checks are needed while you or your child is taking the medicinal products which could cause possible interactions. Examples are listed below (but there are several others):
– some medicines used to treat high cholesterol in the blood (such as atorvastatin, lovastatin, simvastatin);
– medicines used to treat hypertension and heart problems (such as diltiazem, nifedipine, nitrendipine, verapamil, felodipine, amlodipine);
– some medicines used to treat HIV (antiretroviral medicinal products): protease inhibitors (such as amprenavir, atazanavir, indinavir, nelfinavir, ritonavir), non-nucleoside reverse transcriptase inhibitors (such as efavirenz, nevirapine);
– some medicines used to treat microbial infections (such as telithromycin, rifampicin, dapsone);
– medicines used to help you fall asleep: benzodiazepines (such as midazolam, triazolam, diazepam, alprazolam), zaleplon, zolpidem;
– medicines used to prevent/treat epileptic seizures: barbiturates (such as phenobarbital), carbamazepine or phenytoin;
– medicines used after organ transplantation and in autoimmune diseases (such as cyclosporin, tacrolimus);
– sex hormones, including those contained in hormonal contraceptives (such as gestodene, progesterone, estradiol), testosterone;
– glucocorticoids (hydrocortisone, dexamethasone);
– omeprazole (used to treat diseases related to gastric acid production);
– paracetamol (used to treat pain and fever);
– theophylline (used to improve bronchial air flow);
– nefazodone (used to treat depression);
– aprepitant (used to treat nausea);
– some gases (such as enflurane, halothane and isoflurane) used to give a general anaesthetic.

Taking Piperaquine tetraphosphate and dihydroartemisinin Tablets without food and drink
You should take Piperaquine tetraphosphate and dihydroartemisinin Tablets tablets with water only.
You should take this medicine on an empty stomach. You should take each dose no less than 3 hours after the last food intake, and no food should be taken within 3 hours after each dose of Piperaquine tetraphosphate and dihydroartemisinin Tablets.
You can drink water at any time.
You should not take Piperaquine tetraphosphate and dihydroartemisinin Tablets with grapefruit juice due to possible interactions.

Pregnancy and breast-feeding
Tell your doctor if you are pregnant, think you may be pregnant or become pregnant, or if you are breast-feeding.
Piperaquine tetraphosphate and dihydroartemisinin Tablets must not be used in pregnancy if your doctor can give you an alternative medicine. If you receive Piperaquine tetraphosphate and dihydroartemisinin Tablets while pregnant, please note that a pregnancy registry is in place to monitor the pregnancy outcomes.
You should not breast-feed your baby while taking this medicine.
If you are taking folate supplements to prevent possible neural tube birth defects, you can continue taking them at the same time as Piperaquine tetraphosphate and dihydroartemisinin Tablets.
Ask your doctor or pharmacist for advice before taking any medicine during pregnancy or breastfeeding.

Driving and using machines
You can drive or use machines after taking Piperaquine tetraphosphate and dihydroartemisinin Tablets.

3. How you will be given Piperaquine tetraphosphate and dihydroartemisinin Tablets
Always take Piperaquine tetraphosphate and dihydroartemisinin Tablets exactly as your doctor has told you to. You should check with your doctor or pharmacist if you are not sure.

Take this medicine with water and on an empty stomach. You or your child should take each dose at least 3 hours after your last meal. You should also avoid eating until 3 hours after taking Piperaquine tetraphosphate and dihydroartemisinin Tablets.
You can drink water at any time.
If the tablets are difficult to swallow, you can crush and mix them with water; drink the mixture immediately.

A course of Piperaquine tetraphosphate and dihydroartemisinin Tablets lasts 3 consecutive days. Take one dose on each day. You should try to take the dose at about the same time on each of the three days.

The daily dose depends on the patient’s body weight. Your doctor should have prescribed a dose that is appropriate for your weight or your child’s weight as follows:

Body weight (kg)Daily dose (mg)Total number of tablets for treatment
5 to less than 7Half 160 mg/20 mg tablet a day1.5 tablet
7 to less than 13One 160 mg/20 mg tablet a day3 tablets
13 to less than 24One 320 mg/40 mg tablet a day3 tablets
24 to less than 36Two 320 mg/40 mg tablets a day6 tablets
36 to less than 75Three 320 mg/40 mg tablets a day9 tablets
75 to 100Four 320 mg/40 mg tablets a day12 tablets

If you weigh more than 100 kg then follow the dose that your doctor has prescribed.

Vomiting when taking this medicine
If this happens within:
• 30 minutes of taking Piperaquine tetraphosphate and dihydroartemisinin Tablets, the whole dose must be taken again.
• 31-60 minutes, half the dose must be taken again.
If you or your child vomit also the second dose, do not take or give your child another dose. Contact your doctor urgently to obtain an alternative treatment for malaria.

Taking this medicine, if the malaria infection returns
• If you or your child gets another attack of malaria you may take a second course of Piperaquine tetraphosphate and dihydroartemisinin Tablets within one year if your doctor thinks this is a suitable treatment. You or your child must not take more than two courses within one year. If this happens, talk to your doctor. You or your child should not take a second course of Piperaquine tetraphosphate and dihydroartemisinin Tablets within 2 months of the first course.
• If you or your child is infected more than twice in a year, your doctor will prescribe an alternative treatment.

If you or your child takes more Piperaquine tetraphosphate and dihydroartemisinin Tablets than you should
If you or your child takes more than the recommended dose, tell your doctor. Your doctor may suggest special monitoring for you or your child because doses higher than those recommended may have an unwanted, severe effect on your heart (see also section 4).

If you or your child forgets to take Piperaquine tetraphosphate and dihydroartemisinin Tablets
If you or your child forgets to take the second dose of Piperaquine tetraphosphate and dihydroartemisinin Tablets at the right time, take it as soon as you remember. Then take the third (last) dose approximately 24 hours after the second dose.
If you or your child forgets to take the third (last) dose at the right time, take it as soon as you remember.
Never take more than one dose on the same day to make up for a missed dose. Check with your doctor or pharmacist if you are not sure.

If you or your child stops taking Piperaquine tetraphosphate and dihydroartemisinin Tablets
For the medicine to work effectively, you or your child should take the tablets as instructed and should complete the 3 days course of treatment. If you or your child is not able to do this, talk to your doctor or pharmacist.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, Piperaquine tetraphosphate and dihydroartemisinin Tablets can cause side effects, although not everybody gets them. Most of the side effects are not severe and normally disappear within a few days or weeks after treatment.

If you or your child gets a rash, swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing, these may be signs of an allergic reaction. Tell your doctor immediately, or go immediately to the emergency department of your nearest hospital, taking this leaflet with you.

A heart problem, called QT prolongation, can occur while taking Piperaquine tetraphosphate and dihydroartemisinin Tablets and for some days after taking the last dose. This can cause a life-threatening abnormality of the heart rhythm.

Your doctor may take electrical recordings of your heart (electrocardiogram, ECG) while you are being treated and after the last dose is given. Your doctor will advise you when these readings will be taken.

If you notice anything different about your heart rhythm or have symptoms (such as palpitations or irregular heart beat) you should contact your doctor as soon as possible and before the next dose is due.

Side effects in adults
Common (affecting less than 1 in 10 patients but more than 1 in 100)
Anaemia, headache, heart rhythm disturbances (ECG changes or noticing unusually fast heart beats or palpitations), fever, general weakness.

Uncommon (affecting less than 1 in 100 patients but more than 1 in 1000)
Influenza, respiratory infections, poor appetite or loss of appetite, dizziness, convulsions (fits), irregular or slow heart rate, cough, vomiting, abdominal pain, diarrhoea, nausea, inflammation or enlargement of the liver, abnormal liver function tests, itching, pain in the muscles or joints.

Side effects in children
Very common (affecting more than 1 in 10 patients)
Influenza, cough, fever.

Common (affecting less than 1 in 10 patients but more than 1 in 100)
Respiratory infections, ear infection, anaemia, abnormalities in various types of blood cells (white blood cells and platelets), poor appetite or loss of appetite, eye infection, heart rhythm disturbances (change as in adults, ECG changes), abdominal pain, vomiting, diarrhoea, skin inflammation, rash, general weakness.

Uncommon (affecting less than 1 in 100 patients but more than 1 in 1000)
Abnormalities in red blood cells, excessive numbers of platelets, enlargement of some organs (such as liver or spleen), swollen lymph glands, convulsions (fits), headache, abnormal heart sounds (heard by your doctor with a stethoscope), nose bleeds, runny nose, nausea, inflammation of the mouth, inflammation or enlargement of the liver, jaundice, abnormal liver function blood tests, skin itching and inflammation, pain in the joints.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. How Piperaquine tetraphosphate and dihydroartemisinin Tablets is stored
Keep Piperaquine tetraphosphate and dihydroartemisinin Tablets tablets out of the reach and sight of children.
Do not take Piperaquine tetraphosphate and dihydroartemisinin Tablets after the expiry date which is stated on the package after ‘EXP’. The expiry date refers to the last day of that month.
Do not store above 30°C.
Store in the original package in order to protect from light and moisture.
Do not use Piperaquine tetraphosphate and dihydroartemisinin Tablets if you notice the blister package is open.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Further information

What Piperaquine tetraphosphate and dihydroartemisinin Tablets contains
Each film-coated tablet contains
piperaquine tetraphosphate USP      320 mg
(as the tetrahydrate; PQP)
artenimol (artenimol)                        40 mg
Excipients                                           q.s.

The other ingredients are:
Tablet core: pre-gelatinised starch, dextrin, hypromellose (E464), croscarmellose sodium, magnesium stearate (E572).
Film coating: hypromellose, titanium dioxide (E171), macrogol 400.

What Piperaquine tetraphosphate and dihydroartemisinin Tablets looks like and contents of the pack
Piperaquine tetraphosphate and dihydroartemisinin Tablets are white film-coated tablets, embossed and with a break line along the middle.
The tablets come in blister strips containing 3, 6, 9 or 12 tablets.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com