__________________________________________________________________________________________

FLOW CHART FOR ANTI-MALARIAL TREATMENT HOSPITAL SELAYANG

UPDATED 5th November 2013

Prepared by: Tan Li yin Clinical Pharmacist- Medical (Infectious disease), Hospital Selayang
Advised by: Dr Timothy William Infectious Disease Hospital Queen Elizabeth Kota Kinabalu, Sabah Dr Anuradha P. Radhakrishnan Infectious Disease physician Hospital Sg Buloh Dr Benedict Sim Infectious Disease Physician Hospital Sg Buloh Pn Norliza Mat Ariffin Head of Clinical Pharmacist, Hospital Selayang

1|P a g e

2|P a g e

Caution in patients with recent travel to malaria-prone areas or foreigners. Refer to CDC guideline of malaria map application to check resistance profile of species:

http://cdc-malaria.ncsa.uiuc.edu

3|P a g e

Refer pg. 7 for anti-malarial dosages and pg. 8-10 for special population treatment

Please call and refer to ID physician on-call Hosp Sg Buloh (012-3010577) before initiating treatment

PRE-REFERRAL TREATMENT OF MALARIA

SCREEN G6PD DEFICIENCY IN PATIENTS BEFORE STARTING

PRIMAQUINE (refer pg.10)

Treat patients with ONE DOSE of INJ ARTESUNATE 2.4MG/KG BW before REFERRAL. Patients must complete at least 24 hrs of parenteral inj irrespective if able tolerate oral earlier or not)

Malaria cases referred in to hospital

Screen for signs of SEVERE malaria (Refer Table 1 p.6)

SEVERE OR G.I. PROBLEMS (E.G. VOMITING/ CANNOT TOLERATE ORAL)

Treat as SEVERE/COMPLICATED Falciparum: 1) IV ARTESUNATE** AND 2) ORAL DOXYCYCLINE for 1 WEEK

(Doxycycline started when patient condition recovered) AND

3) On day 1, give a SINGLE dose of ORAL PRIMAQUINE BASE 0.25mg/kg/dose (max

45mg/day) 2
\

** If patient condition improves & able to tolerate oral by D3, convert to ORAL RIAMET)
** If unavailable/ treatment failure, consult I.D. physician before starting IV QUININE
4|P a g e

Refer pg. 7 for anti-malarial dosages and pg. 8-10 for special population treatment

Screen for malaria species

SCREEN G6PD DEFICIENCY IN PATIENTS BEFORE STARTING

If malaria species cannot be identified, Start Oral Riamet until species can be identified
.

PRIMAQUINE (refer pg.10)

Malaria species is identified

FALCIPARUM
1) ORAL RIAMET AND 2) On day 1, give a SINGLE dose of ORAL PRIMAQUINE BASE 0.25mg/kg/dose(max 45mg/day) 2

VIVAX/ OVALE
1) ORAL CHLOROQUINE BASE to complete 3 days AND 2) ORAL PRIMAQUINE BASE to complete 14 days

MALARIAE/KNOWESI
-Knowlesi 12,13 : FIRST LINE: ORAL RIAMET SECOND LINE: ORAL CHLOROQUINE BASE -Malariae: ORAL CHLOROQUINE BASE

MIXED MALARIAE
Treat as PLASMODIUM FALCIPARUM

**Treatment failure: refer ID to start ORAL QUININE and ORAL DOXYCYCLINE for 7 DAYS **Treatment failure (CQresistant vivax) refer ID to complete: ORAL RIAMET course (or IV ARTESUNATE for 1 week ) and ORAL PRIMAQUINE BASE for 14 days **IF SEVERE, Treat as COMPLICATED FALCIPARUM MALARIA. For Vivax or Ovale, continue PRIMAQUINE regimen for 14 days

5|P a g e

Table 1: Signs of severe Malaria

Features of severe/complicated Malaria includes at least one of the following: Clinical manifestation: Laboratory findings:

Comments: 1) Refer pg. 7-9 for special populations treatment regimen (renal impaired, liver impaired, pregnancy, paediatrics, G6PD deficiency) 2) High-dose primaquine (0.50.75 mg base/kg body weight per day for 14 days; Maximum 30mg/day),was found to be safe and more effective in radical cure of Primaquine-resistant or tolerant P. Vivax & prevent relapse in non-G6pd deficient patients (compared to lower dosage target of 0.25mg/kg BW) 3) A lower single dose of 0.25 mg base/kg primaquine base (Maximum 45mg/day) has been recommended for persistent sexual parasitemia Falciparum malaria in the updated WHO malaria guideline 2012, as the is found to still be likely in blocking transmission is unlikely to cause hemolytic effects in G6PD variant patients 4) Artesunate found to be superior to quinine in severe malaria with less mortality, less cardiac monitoring (Quinine prolongs QT interval) & less hypoglycemic risk 5) Riamet should be given with a high fat diet meal or drinks to increase absorption (e.g. milk) 6) Plasmodium malariae and Plasmodium knowlesi do not form hypnozoites, so radical cure with primaquine is not required. 7) Oral Dihydroartmesinin plus piperaquine (DHA /PPQ) is an option for first line treatment in Uncomplicated P. falciparum malaria worldwide (WHO guideline, 2010)
6|P a g e

Anti-malarial drug 1) Artemisinin derivatives:

Dosage recommendations IV ARTESUNATE 2.4 mg/kg BW initially (D1), followed by 2.4 mg/kg BW at 12 hours, 24 hours (D2), and subsequently once daily D3 to D7
(Dilute with NS to final conc 10mg/ml then run 3-4ml/min)

- IV ARTESUNATE
(60mg/vial) -ORAL RIAMET (each tab contains 20mg Artemether/ 120mg Lumefantrine)

-ORAL RIAMET (20mg Artemether/120mg Lumefantrine) dosage: - if weight >35kg: 4 tab stat, post 8 hrs, then q12hrs (am, pm) on D2- D3. (Total 24 tablets per treatment course) - if weight 25kg to 34kg: 3 tab stat, then post 8 hrs, then q12hrs (am, pm) on D2-D3 (Total 18 tablets per treatment course)

2) ORAL

CHLOROQUINE
(150mg or 155mg base per tablet- depending on packaging) 3) ORAL

ORAL CHLOROQUINE 10mg/kg stat (t=0) (max 600mg or 620mg* (=4 tablets)), 5mg/kg (max 300mg or 310mg* (=2 tablets)) post 6hrs (t=6), at 24 hrs (D2) & 48 hrs (D3) after the initial dose. (Total dose per course= 25mg/kg BW) (Dosage is expressed in mg of base . Each 250mg chloroquine phosphate tablet = 150mg or 155mg base.. Check with
pharmacist on quantity of base in current packaging)

PRIMAQUINE
(7.5mg base/ tablet)

ORAL PRIMAQUINE BASE -Plasmodium Falciparum : STAT dose- on day 1, Give a SINGLE dose of ORAL PRIMAQUINE BASE 0.25mg/kg/dose (max 45mg/day) - Plasmodium Vivax/ Ovale : ORAL PRIMAQUINE BASE 0.5-0.75mg/kg BW (max 30mg/day) to complete 14 days
(Dosage is expressed in mg of base. Each tablet = 7.5mg base(or 13.1mg primaquine phosphate)

IV QUININE: D1:Load 20mg salt/kg (Max 1400mg per dose) over 4 hours then IV 10mg 4) QUININE salt/kg (Max 700mg/dose) q8 hourly, D2-7: IV Quinine 10mg salt/kg q8h (Inj Quinine (Dilute quinine in 250ml of D5% over 4 hours. Ensure Quinine infusion rate < 5 mg/kg per hour) dihydrochloride 600mg/2ml and ORAL QUININE: 10mg/kg q8hr for 7 DAYS Oral quinine 300mg/tab) 5) ORAL

ORAL DOXYCYCLINE 100mg BD (3.5mg/kg/day) for 7 DAYS

DOXYCYCLINE (100mg/cap)
7|P a g e

Special Dosage recommendations populations

1) Renal impairment
-ARTEMETHER/ LUMEFANTRINE (RIAMET) : no dose modification in mild-moderate impairment. Use with caution in severe impairment (not studied) -ARTESUNATE: no dose modification -QUININE : i) INJECTION:Mild-Moderate: No dosage adjustment; use with caution. Renal Failure: use 1/2 - 1/3 of the dose of Quinine (ref: Updated NAG 2009) ii) ORAL: Clcr 10-50 mL/min: Administer every 8-12 hours
Clcr <10 mL/min: Administer q24 hours Severe chronic renal failure not on dialysis: Initial dose: 600mg (LD) orally followed by 300 mg (MD) every 12 hours Dialysis: Maintain normal dose.Administer dose after dialysis. Not removed by hemo- or peritoneal dialysis; dose as for Clcr <10 mL/minute. Continuous arteriovenous or hemodialysis: Dose as for Clcr 10-50 mL/minute.

-DOXYCYCLINE:
-No dosage adjustment. May accumulate in renal failure. To reduce accumulation, can give once daily with dose 200mg (3.5mg/kg/day) -Not dialysable (hemodialysis)

-CHLOROQUINE:
Clcr 10 mL/min: No dosage adjustment Clcr <10 mL/min: 50% of dose. Hemodialysis effects: Minimally removed by HD Hemodialysis, peritoneal dialysis: Administer 50% of dose. Continuous renal replacement therapy (CRRT): Administer 100% of normal dose.

-PRIMAQUINE: No dosage adjustment

2) Liver impairment

-ARTEMETHER/ LUMEFANTRINE (RIAMET) :no dose modification in mild-moderate impairment. Use with caution in severe impairment (not studied) -ARTESUNATE no dose modification -QUININE : i) INJECTION: Generally, no dosage adjustment; use with caution. However, National Paediatric protocol (3rd ed.) suggests to Reduce IV Quinine dose by one third of total dose in liver
impairment.

ii) ORAL: Mild-to-moderate impairment (Child-Pugh classes A and B): No dosing adjustment required; monitor closely.
Severe impairment (Child-Pugh class C): Avoid use.

-DOXYCYCLINE: No dosage adjustment -CHLOROQUINE: No dosage adjustment -PRIMAQUINE: No dosage adjustment.

3) Pregnancy or Lactation

- PREGNANCY: Pregnant women with symptomatic acute malaria are a high-risk group. Prompt antimalarial treatment is needed.

1) First trimester: Limited data state the antimalarial medicines considered safe are QUININE, CHLOROQUINE & CLINDAMYCIN.
-UNCOMPLICATED FALCIPARUM: Refer to ID physician before starting ORAL QUININE 10MG/KG Q8HR and ORAL CLINDAMYCIN 600MG BD (substituting doxycycline) for 7-10 days (Note: quinine monotherapy indicated if clindamycin not available). Treatment failure: refer case to ID physician - IV ARTESUNATE and ORAL CLINDAMYCIN for 7 days is indicated.
(Note: limited pregnancies in the first trimester (n = 123) found no adverse effects of artemisinin (and partner drugs) on pregnancy or on the fetus & neonates)

-COMPLICATED FALCIPARUM: Refer to ID physician before using IV QUININE and ORAL CLINDAMYCIN 600MG BD. -PLASMODIUM VIVAX: Refer to ID physician. Give CHLOROQUINE (adult dose) OVER 3 DAYS each month for every month until delivery date. Avoid PRIMAQUINE.

2) Second and third trimester: Oral ACT (RIAMET ) or IV ARTESUNATE PLUS ORAL CLINDAMYCIN 600MG BD for 7 days
8|P a g e

OR refer to ID physician before starting ORAL QUININE PLUS ORAL CLINDAMYCIN for 7 days. No adverse effects on mother or fetus found -PLASMODIUM VIVAX: Refer to ID physician. Give ORAL CHLOROQUINE (adult dose) OVER 3 DAYS for each month for every month until delivery date. Avoid PRIMAQUINE in pregnancy. After giving birth (post-partum), mothers need to complete ORAL PRIMAQUINE (adult dose) for 14 days -LACTATION: Lactating women should receive the recommended antimalarial treatment (including ORAL ACTs- RIAMET) for uncomplicated falciparum malaria, except for PRIMAQUINE AND TETRACYCLINE. Antimalarial quantity that enter breast milk and are consumed by the breastfed infant infant are relatively minimal . DOXYCYCLINE is contraindicated in nursing women due to its potential effect on the infants bones and teeth. PRIMAQUINE should not be used in breastfeeding mothers, unless the breastfed infant has been confirmed not to be G6PD-deficient.

4) Paediatric

1) UNCOMPLICATED FALCIPARUM : -ORAL RIAMET(Artemether/Lumefantrine)**: Children 2 mths to 16 years: 5 to 14 kg: 1 tablet at hour 0 and hour 8 on the first day, then 1 tablet twice daily on day 2 &day 3 (total 6 tablets per treatment course) 15 to 24 kg: 2 tablets at hour 0 and hour 8 on the first day, then 2 tablets twice daily on day 2 &day 3 (total 12 tablets per treatment course) 25 to 34kg: 3 tablets at hour 0 and hour 8 on the first day, then 3 tablets twice daily on day 2 and day 3 (total of 18 tablets per treatment course) 35 kg: 4 tablets at hour 0 and hour 8 on the first day, then 4 tablets twice daily on day 2 and day 3 (total of 24 tablets per treatment course) Children >16 years: Refer to adult dosing.

** Give a single dose PRIMAQUINE BASE 0.25mg/kg BW (max 45mg/day) on Day 1 of illness. Check G6PD before giving primaquine.
Use Oral Riamet in children below 10kg for this paediatric group -In treatment failure, refer to ID physician. Recommended treatment failure options: 1) Artesunate 4mg/kg OD plus Clindamycin 10mg/kg/dose BD for 7 days 2) Refer to ID physician before starting Quinine 10mg/kg Q8hr plus Clindamycin 10mg/kg/dose BD for 7 days ** Give a single dose PRIMAQUINEBASE 0.25mg/kg BW (max 45mg/day) on Day 1 of illness. Check G6PD before giving primaquine 2) SEVERE or COMPLICATED FALCIPARUM: -Young children especially those aged below 5 years old are more prone to severe malaria INJ ARTESUNATE : Same as adult dosingD1: IV Artesunate 2.4 mg/kg on admission, then rpt again at 12hrs and 24 hrs thereafter. D2-7: IV Artesunate 2.4 mg/kg OD or switch to oral ACT - Parenteral Artesunate should be given for a minimum of 24h or until patient is able to tolerate orally and thereafter to complete treatment with a complete course of oral ACT (ORAL RIAMET). ALTERNATIVE SECOND LINE TREATMENT: Refer to ID physician before starting IV QUININE: D1:IV Quinine loading 7mg salt/kg over 1 hour followed by Infusion Quinine 10mg salt/kg over 4 hours then 10mg salt/kg q8hourly OR Loading Quinine 20mg salt/kg over 4 hours then IV 10mg salt/kg q8 hourly (Dilute quinine in 250ml of D5% over 4 hours) D2-7: IV Quinine 10mg salt/kg q8h AND ORAL Doxycycline (>8yrs) (3.5 mg/kg OD) OR Oral Clindamycin (<8yrs) (10 mg/kg/dose bd) given for 7 days Note: Quinine infusion rate should not exceed 5 mg salt/kg BW per hour. Change to Oral Quinine if able to tolerate orally. ( Maximum Quinine per dose = 600mg.) Reduce IV Quinine dose by one third of total dose if unable to change to Oral Quinine after 48hours or in renal failure or liver impairment) 3) PLASMODIUM VIVAX/ OVALE: - Severe and complicated P. vivax, knowlesi or malariae should be managed with same treatment as severe Falciparum malaria - ORAL CHLOROQUINE: D1: 10 mg base/kg stat then 5 mg base/kg 6 hours later, D2: 5 mg base/kg OD and D3: 5 mg base/kg OD (Total Chloroquine 25mg base/kg divided over 3 days) PLUS ORAL PRIMAQUINE* 0.5 mg base/kg daily for 14 days (max 30mg/day) 4) PLASMODIUM KNOWLESI/ MALARIAE: - Severe and complicated P. vivax, knowlesi or malariae should be managed with same treatment as severe Falciparum malaria 12,13 - Knowlesi : FIRST LINE: ORAL RIAMET COURSE (refer dose above)
9|P a g e

SECOND LINE: ORAL CHLOROQUINE BASE - D1: 10 mg base/kg stat then 5 mg base/kg 6 hours later, D2: 5 mg base/kg OD and
D3: 5 mg base/kg OD (Total Chloroquine 25mg base/kg divided over 3 days)

- Malariae: ORAL CHLOROQUINE BASE (refer dose above)

5) TREATMENT OF CHLOROQUINE-RESISTANT P. VIVAX, KNOWLESI OR MALARIAE -Refer to ID physician. Recommended treatment options as below: a)ACT (Riamet) should be used for relapse or chloroquine resistant P. vivax. b) For radical cure in P. vivax, ACT must be combined with supervised 14-day oral primaquine therapy. c) Quinine 10mg salt/kg three times a day for 7 days plus oral Primaquine is also effective for chloroquine resistant P. vivax d) Mefloquine 15mg/kg single dose combined with primaquine have been found to be effective. 6) MIXED MALARIA INFECTION Mixed malaria infections are not uncommon. ORAL RIAMET is effective against all malaria species and are the treatment of choice. Treatment with PRIMAQUINE should be given to patients with confirmed P. vivax infection 7) CONGENITAL MALARIA -Congenital malaria is rare. It is acquired from the mother prenatally or perinatally, usually occurring in the newborn of a non-immune mother with P. vivax or P. malariae infection, although it can also be observed with the other malarial species.. -First sign or symptom most commonly occur between 10 and 30 days of age (range: 14hours to several months of age). Signs and symptoms include fever, restlessness, drowsiness, pallor, jaundice, poor feeding, vomiting, diarrhea, cyanosis and hepatosplenomegaly. It can mimic a sepsis like illness. Parasitemia in neonates within 7 days of birth implies trans-placental transmission. Vertical transmission may be as high as 40% and is associated with anemia in the baby. -Baby should been screened for malaria and be treated if parasitemia is present. -Treatment: -ORAL CHLOROQUINE: D1: 10 mg base/kg stat then 5 mg base/kg 6 hours later, D2: 5 mg base/kg OD and D3: 5 mg base/kg OD (Total Chloroquine 25mg base/kg divided over 3 days) -ORAL PRIMAQUINE is not required for treatment as the tissue/ exo-erythrocytic phase is absent in congenital malaria.

5) G6PDdeficient patients

- PRIMAQUINE may cause life threatening haemolysis in individuals with G6PD deficiency. G6PD testing is required before administration of Primaquine. -Mild to moderate G6PD deficiency: PRIMAQUINE BASE regimen of 0.75 mg base/kg BW (maximum 45mg) once per week for 8 weeks is recommended as anti-relapse therapy for P. vivax and P. ovale malaria -Severe G6PD deficiency: PRIMAQUINE contraindicated and should not be used

References: 1) World Health Organization. Guidelines for the treatment of malaria. 2nd ed. Geneva, Switzerland: WHO; 2010. 2) WHO Evidence Review Group: The Safety and Effectiveness of Single Dose Primaquine as a P. falciparum gametocytocide. Malaria Policy Advisory Committee Meeting 11-13 September 2012, WHO HQ Session 5, p11 3 ) Centre of Disease control CDC Malaria guideline 2011 4) White N, Qiao L, et al. Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common. Malaria Journal 2012. http://www.malariajournal.com/content/11/1/418. 11:418 5) Updated WHO Policy Recommendation (October 2012) : Single dose Primaquine as a gametocytocide in Plasmodium falciparum malaria. WHO Global malaria programme. http://www.who.int/malaria/mpac/sep2012/primaquine_single_dose_pf_erg_meeting_report_aug2012.pdf 6) Updated National Malaria Treatment Guideline [updated version], July 2009, Updated Nationsl Antibiotics Guidelin e (NAG) Malaysia, 2009 7) Lexicomp and UpToDate Inc. Wolters Kluwer Health (Philadelphia, PA), 2013. 8) MIMS Drug Information System Malaysia, 2013 9) Ministry of Health (MOH) Paediatric Protocols for Malaysian Hospitals, 3rd edition, 2012. 10) Sabah Malaria Treatment Guidelines, Malaysia 11) Quinine dihydrochloride injection, medicine datasheet (Medsafe), May 2009 (http://www.medsafe.govt.nz/profs/datasheet/q/QuinineDihydrochlorideinj.pdf) 12) William T, Menon J, Rajahram G, Chan L, Ma G, et al. Severe Plasmodium knowlesi Malaria in a Tertiary Care Hospital, Sabah, Malaysia. Emerging Infectious Diseases. www.cdc.gov/eid Vol. 17, No. 7, July 2011 pp. 1248-1253 13) Barber E, William T, Grigg M, Menon J, Auburn S, et al. (2012) Prospective Comparative Study of Knowlesi, Falciparum, and Vivax Malaria in Sabah,Malaysia: High Proportion With Severe Disease From Plasmodium Knowlesi and Plasmodium Vivax But No Mortality With Early Referral and Artesunate Therapy. Clinical Infectious Diseases. [Online] 1-14. Available from: doi: 10.1093/cid/cis902 [Accessed: August 30, 2013] 14) Mefloquine (Lariam, Roche), medicine datasheet (Medsafe), July 2013 (http://medsafe.govt.nz/profs/datasheet/l/lariamtab.pdf) 15) World Health Organization. Management of severe malaria: a practical handbook 3rd ed. Geneva, Switzerland: WHO; 2012.
10 | P a g e