Consumer medicine information

Kodatef

Tafenoquine

BRAND INFORMATION

Brand name

Kodatef

Active ingredient

Tafenoquine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kodatef.

What is in this leaflet?

This leaflet answers some common questions about KODATEF tablets.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking KODATEF tablets against the benefits expected for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What KODATEF is used for

KODATEF is used to prevent malaria in adults for up to six months.

KODATEF is recommended for individuals travelling to areas where malaria is endemic. KODATEF contains the active ingredient tafenoquine.

KODATEF works by killing the parasites that cause malaria.

KODATEF is not addictive.

Ask your doctor if you have any questions about why KODATEF has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you take KODATEF

When you must not take KODATEF

Do not take KODATEF if:

  1. You have been diagnosed or suspect you may have a medical condition known as Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency).
Persons with G6PD deficiency have an increased risk for damage to their red blood cells if they are exposed to certain foods or medicines, including KODATEF. G6PD deficiency is an inherited condition that affects different percentages of individuals based on their ethnicity: about 10% of Africans, 2% of Southeast Asians, and 10% of persons of Mediterranean background (Italian, Greek, or Middle Eastern). If you are unsure whether you have G6PD deficiency, please speak to your doctor. To determine whether you have G6PD deficiency you will need a blood test.
  1. You have had an allergic reaction to any of the ingredients listed at the end of this leaflet.
Some of the symptoms of an allergic reaction may include:
shortness of breath.
wheezing or difficulty in breathing.
swelling of the face, lips, tongue or other parts of the body.
rash, itching or hives on the skin.
  1. You have severe liver disease.
  2. The expiry date (EXP) printed on the package has passed.
If you take this medicine after the expiry date has passed, it may not work as well.
  1. The packaging is torn or damaged.
Do not take KODATEF if the package is torn or shows signs of tampering. If the tamper proof seal has been pealed back or damaged, do not use. Return the damaged packaging to your pharmacist.
  1. You are pregnant.
  2. Do not give this medicine to adolescents or children under the age of 18 years or elderly patients older than 65 years of age.
Safety and effectiveness in children younger than 18 years of age or elderly persons over 65 years of age has not been established.

If you are not sure if you should be taking KODATEF, talk to your doctor or pharmacist.

Before you start to take KODATEF

Tell your doctor if:

  1. You have or have had any health problems, especially the following:
liver problems.
kidney problems.
  1. Known or suspected Glucose-6-phosphate dehydrogenase deficiency (G6PD).
  2. You plan to take or are currently taking metformin or other medicine for type 2 diabetes.
  3. You plan to take or are currently taking a medicine to suppress abnormal rhythms of the heart such as procainamide
  4. You plan to take or are currently taking dapsone for leprosy.
  5. You are pregnant or plan to become pregnant.
  6. You are breastfeeding or intend to breastfeed.
KODATEF may pass into breast milk and may affect your baby; therefore, your doctor will discuss the risks and benefits of taking KODATEF.
  1. You have a psychotic disorder such as schizophrenia.
  2. If you have not told your doctor about any of the above, do so before starting KODATEF.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking KODATEF.

How to take KODATEF

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

How much KODATEF to take

Take KODATEF exactly as your doctor has prescribed. Your doctor will tell you how many KODATEF tablets to take and how often to take them.

Prevention of malaria.

Before entering the malarious area take TWO tablets once daily for THREE days.

After entering the malarious area take TWO tablets of KODATEF once WEEKLY, on the same day of the week, starting ONE WEEK after the last dose taken before entering the malarious area.

After leaving the malarious area take TWO tablets within ONE WEEK of returning. This day should be the same WEEKLY day you took your tablets while in the malarious area.

If you leave the malarious area before starting the weekly dosing regimen, take one last dose 7 days after you finish the pretravel three-day dosing regimen.

Individuals need to complete the full course of KODATEF including starting and final doses.

If you are not sure what to do, ask your doctor or pharmacist.

How to take KODATEF

Swallow tablets whole with a full glass of water.

When to take KODATEF

KODATEF can be taken with or without food.

How long to take KODATEF

Continue taking KODATEF for as long as your doctor tells you to.

KODATEF should be taken as prescribed shortly before entering a malarious area, while still in a malarious area, and for ONE week upon leaving this area. If you leave the malarious area before starting the weekly dosing regimen, take one last dose 7 days after you finish the pre-travel three-day dosing regimen.

Your doctor will advise you of the areas of the world where you may be at risk of contracting malaria.

KODATEF can be taken for up to six months for the prevention of malaria.

If you stay in a malarious area for more than six months, your doctor will tell you what to do to prevent malaria infection.

If you forget to take KODATEF

If one of the weekly KODATEF doses is missed, replace with one KODATEF dose on any day up to the time of the next weekly dose. If two of the weekly KODATEF doses are missed, replace with one KODATEF dose on the day before the next weekly dose. If three or more KODATEF doses are missed, replace with two daily doses before the next weekly dose.

If you think you may have trouble remembering your dose, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much KODATEF, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26 in Australia) for advice, or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking KODATEF

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking KODATEF.

Tell your doctor immediately if you become pregnant while taking KODATEF.

Women of child-bearing potential should use effective contraception while taking KODATEF and for at least three months after taking the last dose.

If you have a psychotic disorder and your symptoms worsen while taking KODATEF, seek medical attention. As malaria can be a fatal disease, you should not stop taking KODATEF without telling your doctor.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do

Do not stop taking KODATEF or change the dose without first checking with your doctor.

Do not let yourself run out of KODATEF while in a malarious area.

Do not give KODATEF to anyone else, even if they are travelling with you.

Tell your doctor if you notice any of the following and they worry you.

These are the more common or general mild side effects:

  • stomach pain or discomfort
  • diarrhoea
  • eye deposits.

These symptoms will go away after you stop taking KODATEF.

KODATEF may cause eye deposits (swirls in the cornea of the eye that can be seen during an eye examination). These do not affect vision (including night vision) and will go away after you stop taking KODATEF.

Stop taking KODATEF and tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you experience any of the following:

seizure (fit) or convulsion.

shortness of breath.

loss of consciousness.

looking pale and yellowing of the skin and/or eyes.

blue or purple coloration of the skin.

abnormal paleness or lack of color of the skin.

feeling of confusion.

fast or abnormal heart rate.

dark colored urine.

pinkish, itchy swellings on the skin, also called hives or nettle rash.

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After taking KODATEF

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they will not keep well.

Keep KODATEF in a cool dry place where the temperature stays below 30°C.

Do not leave it in the car or on window sills. Heat can destroy some medicines.

Keep KODATEF where children cannot reach it. A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking KODATEF, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product Description

What KODATEF looks like

KODATEF tablets are dark pink, capsule shaped, debossed with “TQ100” on one side and plain on the other.

KODATEF tablets (100 mg) are supplied in blister packs. Each blister pack contains 8 tablets. There are one or two blister packs per carton (8 or 16 tablets per carton).

Ingredients

Each KODATEF tablet contains the active ingredient tafenoquine (100 mg) in the form of salt (125.6 mg tafenoquine succinate).

KODATEF tablets also contain:

Microcrystalline Cellulose

Mannitol

Magnesium Stearate

Hypromellose

Titanium dioxide (E171)

Iron oxide red (E172) and

Macrogol/polyethylene glycol 400

KODATEF does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

The Australian Registration Number is AUST R: 293438

This is not all the information available on KODATEF tablets. If you have any more questions or are unsure about anything, ask your doctor or pharmacist.

Manufacturer

KODATEF is distributed in Australia by:

Biocelect Pty Ltd
Level 4, 51 Rawson Street
Epping
NSW 2121
Customer enquiries and Medical Information: 1300 848 628
Website: www.biocelect.com/products/kodatef

KODATEF is a registered trademark of 60 Degrees Pharmaceuticals LLC.

This leaflet was prepared on: 12 September 2018

Published by MIMS January 2019

BRAND INFORMATION

Brand name

Kodatef

Active ingredient

Tafenoquine

Schedule

S4

 

1 Name of Medicine

Tafenoquine succinate.

2 Qualitative and Quantitative Composition

Kodatef tablets contain 125.5 mg/tablet of the active ingredient tafenoquine succinate equivalent to 100 mg of tafenoquine free base.
Tafenoquine succinate, is an off-white to pink/orange/brown crystalline powder and exhibits the highest solubility at pH 1 (25°C and 37°C), pH 2 (37°C) and pH 4 (37°C), and negligible solubility at all other tested pH values at 25°C and 37°C.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Kodatef tablet is a dark pink, capsule shaped, film coated tablet debossed with "TQ100" on one side and plain on the other. The tablets are for oral administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Malaria prophylaxis.

Kodatef (tafenoquine) is an antimalarial indicated for the prevention of malaria in adults 18 years of age and above for up to 6 months of continuous dosing (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

The recommended dosing regimen for Kodatef is shown in Table 1.
All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing tafenoquine (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Pregnancy should be excluded prior to the use of tafenoquine in females of child bearing potential (see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation).
Kodatef tablets should be swallowed whole and not chewed or broken apart. Kodatef tablets can be taken with or without food although Kodatef taken with food may be associated with better gastrointestinal tolerance.
Dosage adjustment for persons with renal impairment, hepatic impairment and dialysis has not been studied in clinical trials.
Kodatef is not intended for treatment of acute malaria. Relevant clinical guidelines should be used for management of acute malaria, including subjects who develop acute malaria while taking Kodatef for prophylaxis or in instances of relapse of malaria following cessation of prophylaxis with Kodatef.
Malaria prophylaxis with Kodatef consists of loading, maintenance and terminal dosing. Kodatef should only be used for a maximum of 6 months of continuous dosing. No more than a total of 28 doses should be consumed in a 6 month period.
There are no data on repeated use of Kodatef for malaria prophylaxis after the initial use.
Individuals need to complete the full course of Kodatef including loading and terminal doses. If leaving the malarious area before the start of the maintenance regimen, a single terminal dose should be taken 7 days after the last dose of the loading regimen.

Missed doses.

See Table 2.

4.3 Contraindications

Individuals with G6PD deficiency or unknown G6PD status due to the risk of haemolytic anaemia (see Section 4.4 Special Warnings and Precautions for Use).
Pregnancy and Lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Subjects with current or history of psychosis (see Section 4.4 Special Warnings and Precautions for Use).
Known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any other component of Kodatef formulation. Due to the long half-life of tafenoquine (up to 17 days), hypersensitivity reactions may be delayed in onset and/or duration.

4.4 Special Warnings and Precautions for Use

G6PD enzyme deficiency.

G6PD deficiency should be excluded before prescribing Kodatef due to the risk of haemolytic anaemia in patients with G6PD deficiency. Physicians need to be aware of residual or unrecognised risk of haemolysis due to limitations of the G6PD tests. In clinical trials, declines in haemoglobin levels have been reported in patients with normal G6PD enzyme levels. Monitor patients for clinical signs or symptoms of haemolysis. Advise patients to discontinue Kodatef and seek medical attention if signs of haemolysis occur.

Psychiatric effects.

In patients receiving Kodatef in clinical trials, adverse psychiatric reactions included sleep disturbances (2.5%), depression/depressed mood (0.3%), and anxiety (0.2%). Kodatef was discontinued in one subject with a reported adverse reaction of suicide attempt (0.1%) deemed unrelated to Kodatef by the Investigator. Subjects with a history of psychiatric disorders were excluded from the pivotal clinical study (trial 033) supporting the use of Kodatef for prophylaxis of malaria. Serious psychiatric disorders such as psychosis and depression have been associated with some quinoline anti-malarial agents.
Kodatef should not be used in subjects with a history of serious psychosis or current psychotic symptoms, delusions or hallucinations. If psychosis or other serious psychiatric events occur while taking Kodatef, urgent medical advice should be sought.

Haematological effects.

Haemoglobin decreases by 0.66 g/dL have been frequently reported in clinical trials of Kodatef. Asymptomatic elevations in methaemoglobin, characteristically increases to > 1% but below 10% (a level associated with hypoxia), have been observed in the clinical trials of Kodatef. Discontinuation of Kodatef treatment is recommended if signs and symptoms of methaemoglobinemia occur, followed by medical advice and appropriate medical therapy.

Gastrointestinal effects.

Gastrointestinal effects including diarrhoea (13% of subjects), vomiting (4%), and gastroesophageal reflux disorder (2%), occurred at a greater frequency in Kodatef-treated subjects than in placebo subjects in clinical trials. Administration of Kodatef with food may ameliorate these gastrointestinal effects.

Use in hepatic impairment.

Tafenoquine pharmacokinetics have not been studied in patients with hepatic impairment. Patients with serum levels of ALT > 60 U/L and total bilirubin levels > 2.0 mg/dL were excluded or infrequently entered in the pivotal clinical trials (mean ALT = 28 U/L, SD=12; mean total bilirubin = 0.5 mg/dL, SD=0.3).

Use in renal impairment.

Tafenoquine pharmacokinetics have not been studied in patients with renal impairment. Patients with serum creatinine > 1.8 mg/dL were excluded from the pivotal clinical trials.

Use in the elderly.

Clinical trials did not include sufficient numbers of subjects 65 years of age and over to determine if they respond differently than younger subjects.

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

The use of Kodatef may influence the results of certain laboratory tests including biochemical parameters of the liver and kidneys and haematology parameters. These changes, which are expected due to the oxidative nature of 8-aminoquinoline drugs, generally remain within the normal laboratory range of each parameter. Biochemical parameter changes may include mild ALT elevations (> 60 U/L) and serum creatinine elevations > 1.8 mg/dL. Change in haematology parameters, may specifically include a reduction of haemoglobin > 0.66 g/dL and methaemoglobin increases to > 1%. Methaemoglobin does not increase to as much as 10%, a level associated with hypoxia.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Kodatef may inhibit drug transporters in the kidney. Since inhibition of these transporters may lead to increased exposure to medications that they excrete, when Kodatef is co-administered with procainamide, it may be advisable to re-evaluate the safety and/or efficacy of procainamide.
Tafenoquine inhibited the in vitro transport of [14C] metformin via OCT2, MATE1, and MATE2-K. Clinical predictions indicate there may be a potential, but low risk of lactic acidosis in subjects who receive tafenoquine and metformin concomitantly, due to an increased exposure to metformin arising from this interaction.

Treatment with other potentially haemolytic drugs.

Drugs including dapsone may cause haemolysis in G6PD-normal individuals. It is possible that dapsone in combination with Kodatef might cause haemolysis in G6PD-normal individuals. If dapsone is co-administered with Kodatef, monitor urine for dark colour and perform periodic checks of hematocrit.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Tafenoquine had no effects on mating, estrous cycles, sperm motility, sperm count or morphology in rats dosed with tafenoquine at up to 15 mg/kg/day (approximately 6 times the clinical exposure based on AUC). However, the number of corpora lutea was decreased at 15 mg/kg/day, resulting in lower numbers of implantations and viable foetuses. There was no effect on fertility at 5 mg/kg/day (approximately 2 times the clinical exposure based on AUC).
(Category C)
Kodatef is contraindicated in pregnancy because the G6PD status of the foetus is unknown.
Kodatef was not teratogenic in the rat or rabbit. However, Kodatef may cause foetal harm when administered to a pregnant woman if the foetus is G6PD-deficient and should not be taken in pregnancy. There are no adequate and well-controlled trials in pregnant women. If pregnancy is detected while taking Kodatef, discontinue Kodatef and seek medical advice.
Furthermore, females of reproductive potential should use effective contraception during malaria prevention administration and for five half-lives (three months) after the end of treatment.
The effects of tafenoquine on labour and delivery are unknown.
Tafenoquine resulted in dose related abortions when given orally to pregnant rabbits during organogenesis (gestational day 6 to 18), at doses of 7 mg/kg (about 4.5 times the clinical dose on a mg/m2/week basis) and above. Doses higher than 7 mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In a similar study in rats, doses of 3, 10, or 30 mg/kg/day resulted in maternal toxicity but no foetotoxicity, at the high dose (equivalent to 10 times the clinical dose on a mg/m2/week basis). There was no evidence of malformations in either species.
Women taking Kodatef should stop breastfeeding. A G6PD-deficient infant may be at risk for haemolytic anaemia from exposure to Kodatef through breast milk. Check infant's G6PD status before breastfeeding recommences.
In rats given oral doses of tafenoquine during gestation and lactation, decreased body weight gain, slightly delayed eye opening and decreased rearing activity of offspring, associated with maternal toxicity were observed at 18 mg/kg/day (approximately 8 times the clinical exposure based on AUC).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The following adverse reactions are discussed in greater detail in other sections of the Product Information:
Gastrointestinal effects (see Section 4.4 Special Warnings and Precautions for Use).
Haematological effects (see Section 4.4 Special Warnings and Precautions for Use).
Drug-drug interactions (see Section 4.4 Special Warnings and Precautions for Use).
Treatment with other potentially haemolytic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Clinical trial experience.

The safety of tafenoquine was studied in clinical trials at various doses and regimens in 3,184 subjects. The recommended Kodatef malaria prevention regimen was evaluated in 825 subjects in 5 controlled clinical trials (Trials 043, 045, 030, 033, and 057). The mean duration of exposure to Kodatef in these five clinical trials was 21 weeks (range 10-29 weeks). Trial 043, 045 and 030 were conducted in healthy, semi-immune, indigenous African volunteers in Ghana or Kenya and were placebo-controlled; a mefloquine arm was included in Trials 045 and 030 as a benchmark. Possible asymptomatic parasitaemia was cleared prior to initial receipt of trial drugs in these African studies. Trial 033, an active comparator (mefloquine) controlled trial was conducted in healthy Australian soldiers deployed in East Timor (now Timor Leste) for a peace-keeping operation at which time trial drugs were administered. A placebo-controlled Trial 057 was a renal and ophthalmic safety trial conducted in healthy volunteers in the United States and United Kingdom. The mean age of the subjects included in the five trials was 29 years (range 17 to 69 years); 84% were male. The number of randomised placebo subjects in these trials plus one other (Trial 044) was 396. 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 rates observed in practice.

Serious adverse events and treatment discontinuations.

A total of 49 serious adverse events (SAEs) were reported in tafenoquine-treated subjects (5.9 per 100 subjects) compared to 23 SAEs in placebo-treated subject (5.8 per 100 subjects). Of the 49 SAEs in tafenoquine-treated subjects, only 23 were SAEs that were considered "treatment-related" (includes unlikely, possibly, or probably treatment-related). Of these 23 SAEs: seven were an eye disorder, 5 were decreased glomerular filtration rate, 4 were an infection or infestation, 4 were gastrointestinal disorders, 2 were a nervous system disorder, and 1 was a blood/lymphatic tissue disorder. Of the 23 SAEs in placebo subjects, 10 were considered "treatment-related", affecting 9 subjects. Of these 10 treatment-related SAEs: 1 was an eye disorder, 2 were decreased glomerular filtration rate, 3 were an infection or infestation, 1 was a gastrointestinal disorder, 1 was a nervous system disorder, and 2 were general disorders and administration site conditions.
The most common treatment-related adverse reactions leading to treatment discontinuation in tafenoquine-treated subjects were increased ALT (6 subjects), decreased haemoglobin (3 subjects), and decreased GFR (2 subjects). Only 1 or 2 subjects were discontinued due to AEs in other body systems. The most common treatment-related adverse reactions leading to treatment discontinuation in placebo-treated subjects were increased ALT (1 subject), decreased haemoglobin (1 subject), and decreased platelet count (1 subject). In addition, 1 placebo-treated subject was discontinued for headache and 1 for metamorphopsia.

Eye findings.

Vortex keratopathy (specifically, corneal deposits that can only be detected during a medical examination) was reported in 21% to 93% of subjects receiving Kodatef for 3-6 months in the three trials that included ophthalmic evaluations. The vortex keratopathy did not result in any apparent functional visual changes, including no loss of night vision, and resolved within 1 year after drug cessation in all subjects. Retinal abnormalities were noted in less than 1% of subjects receiving Kodatef. A total of 7 ocular adverse events were reported to regulatory authorities, 5 reports of vortex keratopathy after the initial findings and 2 reports of retinal disorders.

Laboratory abnormalities.

Methaemoglobinemia.

Asymptomatic methaemoglobin elevations were observed in 13% of subjects receiving Kodatef.

Haemoglobin decrease.

Haemoglobin decreases of ≥ 3 g/dL were observed in 2.3% of subjects receiving Kodatef.

Common adverse events.

Adverse reactions occurring in ≥ 1% of subjects in the Kodatef group in the active-control Trial 033 conducted in military personnel deployed to malaria endemic areas are presented in Table 3.
Adverse reactions occurring in ≥ 1% of subjects in the Kodatef group in the placebo-controlled pooled data from Trials 043, 045, 030 and 057 are presented in Table 4.

Adverse events reported in < 1% of subjects receiving Kodatef in trials 030, 033, 043, 045 and 057.

The following selected adverse reactions were reported in subjects receiving Kodatef in Trials 030, 033, 043, 045 and 057 at a rate of less than 1%.

Blood and lymphatic system disorders.

Haemolytic anaemia, anaemia, thrombocytopenia.

Ear and labyrinth disorders.

Hyperacusis, Meniere's disease.

Eye disorders.

Night blindness, photophobia, blurred vision, visual acuity reduced, visual impairment, vitreous floaters.

Hepatobiliary disorders.

Hyperbilirubinaemia, jaundice cholestatic.

Immune system disorders.

Hypersensitivity.

Investigations.

Blood bilirubin increased, blood creatinine increased, glomerular filtration rate decreased.

Nervous system disorders.

Amnesia, coordination abnormal, hyperesthesia, hypoesthesia, somnolence, syncope, tremor, visual field defect.

Psychiatric disorders.

Agitation, neurosis.

Skin and subcutaneous tissue disorders.

Urticaria.

Reporting suspected adverse events.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There were no reported cases of Kodatef overdose. However, based on clinical experience with individual doses above 200 mg, early symptoms of Kodatef overdose are likely to be gastrointestinal (nausea, vomiting, diarrhoea, and abdominal pain). Haematologic events (haemolytic anaemia and methaemoglobinaemia), may also be seen. Haemolytic anaemia is also to be expected if normal Kodatef doses are administered in error to subjects deficient in G6PD.
Patients should contact their health care provider if they have darker lips or urine (see Section 5 Pharmacological Properties), as these may be signs of haemolysis or methaemoglobinaemia.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tafenoquine kills the developing asexual, developing exoerythrocytic, and latent hypnozoites of malaria parasites. The mechanism of action is unknown, but is hypothesised to involve redox reactions.

Safety pharmacology.

In vitro studies with tafenoquine suggested potential effect on heart conductance, as it inhibited hERG tail current in a dose-dependent manner (IC50 0.51 microgram/mL) and at 100-fold higher concentrations (46.4 microgram/mL) caused a non-specific effect on the conduction through heart purkinje fibres of the dog. In vivo, tafenoquine caused systemic vasodilation when given by IV infusion to anaesthetised dogs but at oral doses up to 16 mg/kg had no cardiovascular effect in the conscious dog. The dog AUC0-1 week of 116 microgram.hr/mL following 16 mg/kg is approximately five-times higher than the clinical AUC following a clinical dose of 600 mg.
The effect of tafenoquine on the QT interval was evaluated in a trial of healthy adult subjects. In this trial, subjects received once daily 400 mg (2 times the approved recommended dosage) doses of tafenoquine for 3 days. The results suggest that the mean increase in the QTcF interval for tafenoquine is less than 20 msec.

Clinical trials.

The use of Kodatef for prophylaxis of malaria is supported by single pivotal trial 033.
Trial 033 compared tafenoquine with mefloquine for the prophylaxis of both Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) malaria in healthy non-immune Australian soldiers deployed to East Timor (now Timor-Leste).
The trial was carried out from 1999-2000. All applicable ethical and informed consent procedures were appropriately undertaken.
The trial was divided into two phases. The first, or prophylactic phase, consisted of a 26-week period during deployment where subjects received prophylactic trial medication (tafenoquine 200 mg or mefloquine 250 mg). At the end of the deployment to the malarious area and once the subjects had returned to barracks in Townsville, Australia, the subjects entered a 24-week relapse follow-up phase. During this follow-up phase, subjects who had been on mefloquine prophylaxis received 14-days of primaquine (15 mg bid) while subjects on tafenoquine prophylaxis received placebo capsules for 14 days.
Subjects with documented G6PD enzyme deficiency or a history of psychiatric disorders and/or seizures were excluded, as well as subjects with any significant medical history or concurrent medical condition. All subjects (N=654) were healthy at baseline with an age range of 18-47 years. Mean age was 25 ± 5 years in the tafenoquine group and 26 ± 6 years in mefloquine group. Subjects were mostly male (97%) and of white ethnicity (99%).
The primary efficacy endpoint was prophylactic failure (Table 5): parasitologic and clinical failure during the 26-week prophylactic phase. The protocol-defined principal efficacy analysis was based on the per-protocol (PP) population, which consisted of all randomised subjects who satisfied inclusion/exclusion criteria and subsequently adhered to the protocol. A very high compliance to trial drugs was observed in the trial - 100% for the loading dose, 99% for the weekly regimens and 96% during the relapse follow-up phase. No subject was a prophylactic failure during the prophylactic phase. Historic control data indicate that 7.9% of subjects would have become infected (6.9% with Pv, 1.0% with Pf) under those conditions.
In the 24 week follow up phase after leaving the endemic region, and after receiving no further drug (tafenoquine group), or standard post-exposure prophylaxis with primaquine (mefloquine group), there were four cases of Pv malaria in the tafenoquine group and one case of Pv malaria in the mefloquine group (Table 6).
The failure rate due to Pv relapse was 0.9% for the tafenoquine group and 0.7% for the primaquine group. The time to relapse after the last dose of tafenoquine or mefloquine was 12-20 weeks for the 4 tafenoquine failures and 12 weeks for the 1 mefloquine-then-primaquine failure. All 5 cases were Pv malaria.
The relapse follow-up was extended for another 6 months (a total of 12 months post-prophylactic phase). There were 3 more cases of malaria in the tafenoquine group and one case of malaria in the mefloquine/primaquine group during this 6-month extension, bringing to a total of 7 Pv relapses in the tafenoquine group and 2 Pv relapses in the mefloquine/primaquine group during the 12 months relapse follow-up after the end of prophylactic phase.

5.2 Pharmacokinetic Properties

A population PK analysis in healthy subjects was conducted consolidating clinical PK data from Trials 001, 002, 003, 004, 005, 014, 015, 033, 044 and 058. Covariates common to all 10 trials were age, weight, race, sex and meal schedule. The analysis comprised 866 participants across the trials. The total analysis population was 93.3% male; median age 25 years, mean weight 75.0 kg and 72.3% Caucasian/white. The majority of participants (89.4%) took tafenoquine under fed conditions (i.e. after a meal).
A one-compartment PK model with first-order absorption and elimination processes was specified in the NONMEM control file and was parameterised in terms of apparent CL/F, V/F and ka. Key pharmacokinetic parameters from the population PK analysis and from Trial 051 data are shown in Table 7.

Absorption.

Tafenoquine plasma concentrations were generally higher following administration of a single dose of tafenoquine under fed compared with fasting conditions, with mean fed: fasted ratios of 1.41 (AUC) and 1.31 (Cmax). Tmax and t½ were similar under fasting and fed states. However, population PK analyses demonstrated that after the recommended regimen of 200 mg/day times 3 days for loading followed by 200 mg weekly, trough tafenoquine values even in the non-fed state were above the value of 80 nanogram/mL (the minimum target trough value for prevention of symptomatic malaria in non-immune individuals) by the end of the loading dose. By the sixth weekly dose, exposure in the fasted state is predicted to equal exposure in the fed state.

Distribution.

In healthy male volunteers administered one dose of 100 mg, 200 mg, or 400 mg while fasting, blood and calculated RBC concentrations were 2.0 and 3.4 times higher than corresponding plasma concentrations, and there was no change in RBC accumulation over time. In humans, > 99.5% of tafenoquine is bound to plasma protein.

Metabolism.

In human biomaterials studied in vitro, minimal metabolism of tafenoquine occurred. When tafenoquine 400 mg per day for three days was administered to humans, only parent tafenoquine was extractable in plasma drawn 80 hours after the first dose.

Excretion.

The major route of excretion in the rat, dog and monkey was via the faeces and to a lesser extent via the urine. Overall excretion of radioactivity in animals was slow. In bile-cannulated animals, equal amounts were recovered in bile and faeces in dogs (20% of dose in 7 days) and 5% of dose in bile and 75% of dose in faeces in rats in 4 days. Human radiolabeled mass balance studies have not been conducted to characterise the clinical excretion of tafenoquine.

Dose-PK relationships.

Following administration of a single dose to healthy males, AUC and Cmax were dose-proportional. When healthy volunteers received 10 weekly administrations of 200 mg without a loading dose while fasting, the accumulation ratio was approximately 4.

PK-PD relationships.

Trials in non-immune persons (those without prior malaria exposure), a population similar to the population for which malaria prevention is intended, showed that symptomatic breakthrough of malaria only occurred when tafenoquine plasma concentrations were < 50 nanogram/mL. Consequently, a precautionary plasma concentration of 80 nanogram/mL was selected as the minimum target trough value for prevention of symptomatic malaria development in non-immune individuals. Population PK analysis predicts that the recommended prevention regimen will achieve trough levels > 80 nanogram/mL in > 95% of subjects.

Drug-drug interactions.

Tafenoquine does not significantly inhibit or induce CYP2D6, CYP3A4, CYP2C9 or CYP1A2, since in phase 1 trials, the PK parameters of the CYP2D6 substrate desipramine, the CYP3A4 substrate midazolam, the CYP2C9 substrate Flurbiprofen and the CYP1A2 substrate caffeine were unaffected by co-administration of tafenoquine.
Tafenoquine was a potent inhibitor of renal multidrug and toxin extrusion transporters (MATE) and organic cation transporter 2 in vitro. Since inhibition of these transporters may lead to increased exposure to medications that they excrete, when tafenoquine is co-administered with procainamide, it may be advisable to re-evaluate safety and/or efficacy of procainamide.
Tafenoquine inhibited the in vitro transport of [14C] metformin via OCT2, MATE1, and MATE2-K. Risk assessments based on systemic concentrations of tafenoquine at therapeutic doses, compared with the metformin IC50 values derived from in vitro transporter inhibition studies, were conducted and indicated a potential, but low, drug interaction risk with OCT2, MATE1 and/or MATE2K substrates. Clinical predictions indicate there may be a potential, but low, risk of lactic acidosis in subjects who receive tafenoquine and metformin concomitantly, due to an increased exposure to metformin arising from this interaction.

5.3 Preclinical Safety Data

Genotoxicity.

The mutagenic and clastogenic potential of tafenoquine has been assessed in bacterial gene mutation assays and in vitro gene mutation assays in mammalian cells (mouse lymphoma cells and Chinese hamster ovary cells), in vitro chromosome aberration assays in Chinese hamster ovary cells, and one mouse in vivo micronucleus study. Based on these studies, tafenoquine is not considered to present a genotoxic risk to humans.

Carcinogenicity.

Two two-year oral carcinogenicity studies were performed; 1 in the mouse and 1 in the rat. Oral administration of doses up to 1.0 mg/kg/day (approximately 0.3 times the clinical exposure based on AUC) for 2 years produced no clear evidence of an increase in the incidence of tumours in treated mice of either sex. Tafenoquine administration was associated with an increase in the incidence of renal tumours and hyperplasia in male rats following administration of 1.0 and/or 2.0 mg/kg/day (0.5 times the clinical exposure based on AUC). The exact mechanism behind renal tumor development is unknown but may be the result of multi-factorial, non-genotoxic modes of action, possibly potentiated by chronic progressive nephropathy (CPN). CPN is a spontaneous age-related disease that occurs at a high incidence in rat strains used in preclinical toxicology studies, exhibiting a predisposition in male rats. The relevance of these findings for a carcinogenic risk in humans is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Kodatef also contains: microcrystalline cellulose, mannitol, magnesium stearate, hypromellose, titanium dioxide (E171), iron oxide red (E172) and macrogol/polyethylene glycol 400.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below +30°C. Protect from moisture. Dispense only in the original carton.

6.5 Nature and Contents of Container

Kodatef 100 mg tablets are packed in polyamide aluminum and PVC formable laminate backed blisters with a peelable polyethylene terephthalate aluminum foil and paper cover. Each blister card contains eight tablets. Each carton contains 8 or 16 tablets (one or two blister cards).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 8-[(4-Amino-1-methylbutyl) amino]-2,6-dimethoxy-4-methyl-5-[3- (trifluoromethyl) phenoxy]quinoline succinate.
Molecular weight: 463.49 (free base anhydrous); 581.58 (succinate salt).
Molecular Formula: C24H28F3N3O3.C4H6O4.

CAS number.

106635-80-7 (tafenoquine free base) and 106635-81-8 (tafenoquine succinate) (Source Chemical Book).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes