PRIMAQUINE PHOSPHATE- primaquine phos phate tablet

Bays hore Pharmaceuticals , LLC

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PRIMAQUINE
PHOSPHATE
TABLETS, USP

WARNING
PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE
COMPLETE CONTENTS OF THIS LEAFLET BEFORE PRESCRIBING PRIMAQUINE
PHOSPHATE.

DESCRIPTION
Primaquine phosphate is 8-[(4-Amino-1-methylbutyl)amino]-6-methoxyquinoline phosphate, a synthetic
compound with potent antimalarial activity. Each tablet contains 26.3 mg of Primaquine phosphate
(equivalent to 15 mg of primaquine base). The dosage is customarily expressed in terms of the base.
Inactive Ingredients: Microcrystalline Cellulose, Pregelatinized Starch, Lactose Monohydrate,
Magnesium Stearate, Purified water, Hypromellose, Opadry Purple, Titanium Dioxide, Macrgol/PEG,
FD&C Red #40 and FD&C Blue #2.

CLINICAL PHARMACOLOGY
Primaquine phosphate is an 8-aminoquinoline compound which eliminates tissue (exoerythrocytic)
infection. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which
are responsible for relapses in vivax malaria. Primaquine phosphate is also active against gametocytes
of Plasmodium falciparum.

INDICATIONS AND USAGE

Primaquine phosphate is indicated for the radical cure (prevention of relapse) of vivax malaria.

CONTRAINDICATIONS
Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency (see WARNINGS).
Pregnant women (see WARNINGS, Usage in Pregnancy).
Primaquine phosphate is contraindicated in acutely ill patients suffering from systemic disease
manifested by tendency to granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. The
drug is also contraindicated in patients receiving concurrently other potentially hemolytic drugs or
depressants of myeloid elements of the bone marrow.
Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which
are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is
contraindicated. Similarly, Primaquine should not be administered to patients who have received
quinacrine recently, as toxicity is increased.

WARNINGS
Discontinue the use of Primaquine phosphate promptly if signs suggestive of hemolytic anemia occur
(darkening of the urine, marked fall of hemoglobin or erythrocytic count).
Hemolytic reactions (moderate to severe) may occur in individuals with glucose-6-phosphate
dehydrogenase (G-6-PD) deficiency and in individuals with a family or personal history of favism.
Areas of high prevalence of G-6-PD deficiency are Africa, Southern Europe, Mediterranean region,
Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to
develop hemolytic anemia (due to a congenital deficiency of erythrocytic glucose-6-phosphate
dehydrogenase) while receiving Primaquine and related drugs.

Hemolytic anemia and G6PD deficiency

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing has to be
performed before using primaquine. Due to the limitations of G6PD tests, physicians need to be aware
of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk
should be available.
Primaquine should not be prescribed for patients with severe G6PD deficiency (see
CONTRAINDICATIONS).
In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an
assessment of the risks and benefits of using primaquine. If primaquine administration is considered,
baseline hematocrit and hemoglobin must be checked before treatment and close hematological
monitoring (e.g. at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should
be available.
When the G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine
must be based on an assessment of the risks and benefits of using primaquine. Risk factors for G6PD
deficiency or favism must be assessed. Baseline hematocrit and hemoglobin must be checked before
treatment and close hematological monitoring (e.g. at day 3 and 8) is required. Adequate medical support
to manage hemolytic risk should be available.
Discontinue the use of primaquine phosphate promptly if signs suggestive of hemolytic anemia occur
(darkening of the urine, marked fall of hemoglobin or erythrocytic count).
Hemolytic reactions (moderate to severe) may occur in individuals with G6PD deficiency and in
individuals with a family or personal history of favism. Areas of high prevalence of G6PD deficiency
are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People
from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency
of erythrocytic G6PD) while receiving primaquine and related drugs.

Us age in Pregnancy
Safe usage of this preparation in pregnancy has not been established. Therefore, use of it during
pregnancy should be avoided except when in the judgment of the physician the benefit outweighs the
possible hazard.

Us e in Females and Males of Reproductive Potential

Pregnancy Testing
Sexually active females of reproductive potential should have a pregnancy test prior to starting
treatment with primaquine.

Contraception
Patients should avoid pregnancy during treatment. The use of effective contraception is recommended
during treatment and after the end of treatment as follows: Advise sexually active females of
childbearing potential to use effective contraception (methods that result in less than 1% pregnancy
rates) when using primaquine and after stopping treatment until completion of an ongoing ovulatory
cycle (e.g., up to next menses). Advise treated males whose partners may become pregnant to use a
condom while on treatment and for 3 months after stopping treatment with primaquine.

Lactation
It is not known whether primaquine is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants from
primaquine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.

PRECAUTIONS

Blood Monitoring
Since anemia, methemoglobinemia, and leukopenia have been observed following administration of
large doses of primaquine, the adult dosage of 1 tablet (= 15 mg base) daily for fourteen days should not
be exceeded. In G6PD normal patients it is also advisable to perform routine blood examinations
(particularly blood cell counts and hemoglobin determinations) during therapy.
If primaquine phosphate is prescribed for an individual who has shown a previous idiosyncratic
reaction to primaquine phosphate as manifested by hemolytic anemia, methemoglobinemia, or
leukopenia; an individual with a family or personal history of hemolytic anemia or nicotinamide adenine
dinucleotide (NADH) methemoglobin reductase deficiency, the person should be observed closely. In
all patients, the drug should be discontinued immediately if marked darkening of the urine or sudden
decrease in hemoglobin concentration or leukocyte count occurs.

Potential Prolongation of QT Interval

Due to potential for QT interval prolongation, monitor ECG when using primaquine in patients with
cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia
and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT
interval prolonging agents (see PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS, and
OVERDOSAGE).

Carcinogenes is , Mutagenes is , Impairment of Fertility

No carcinogenicity studies have been conducted with primaquine. No fertility studies have been
conducted with primaquine. Primaquine is reported in the literature to be a weak genotoxic agent which
elicits both gene mutations,1 chromosomal damage and DNA strand breaks.2 The publications reported
positive results in the in vitro reverse gene mutation assays using bacteria (Ames test)3,4 and in the in
vivo studies using rodents (mouse bone marrow cell sister chromatid exchange, mouse bone marrow
cell chromosome abnormality, and rat DNA strand breaks in multiple organs).2,5 The genotoxicity data
obtained in vitro and in rodent models are suggestive of a human risk for genotoxicity with primaquine
administration (see WARNINGS, Usage in Pregnancy).

Animal Pharmacology and/or Animal Toxicology

Literature data on reproductive toxicology identified embryo-fetal development toxicity. In studies in
rats, teratogenic effects on fetus were observed (see WARNINGS, Usage in Pregnancy).
In the first reproductive toxicity study,6 primaquine was administered orally to rats between gestation
day (GD) 6 and GD15 at dose levels of 10.3, 30.8 and 61.5 mg/kg/day (as base) (representing
approximatively 7, 20 and 40 times the human dose [HD] on a body surface area comparison) when
considering a human body weight of 60 kg). High dose levels induced death of pregnant females in
almost all cases, while lower dose levels caused maternal toxicity. At cesarean section, embryo
resorption, a decrease in fetal survival rate and body size, internal abnormalities (including
hydrocephalia, heterotaxia), and an increase in skeletal variations were observed at the mid dose level.
There were no fetal abnormalities at the low dose level providing a potential safety margin of at least 7
times the recommended clinical dose.
For the second reproductive toxicity study,7 6 to10 animals per group were used. Dose levels of 0.57,
5.7, 11.4 and 34 mg/kg/day of primaquine (as base) (representing approximatively 0.4, 4, 7 and 22 times
the HD on a body surface area comparison) were administered orally to Sprague Dawley rats between
GD8 and GD16, or of 57 mg/kg only once on GD13 (representing more than 37 times the HD on a body
surface area comparison). A total of 1/7 and 4/6 pregnant females at 34 mg/kg/day and at 57 mg/kg,
respectively, died. Primaquine-associated teratogenic malformations (including cleft palate and small
chin) were observed in 4/54 fetuses in the 57 mg/kg single-dose group.

Drug Interactions
Caution is advised if Primaquine is used concomitantly with other drugs that prolong the QT interval
(see PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE).

Geriatric Us e
Clinical studies of Primaquine did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.

ADVERSE REACTIONS
Gas trointes tinal: nausea, vomiting, epigastric distress, and abdominal cramps.
Hematologic: leukopenia, hemolytic anemia in glucose-6-phosphate dehydrogenase (G-6-PD)
deficient individuals, and methemoglobinemia in nicotinamide adenine dinucleotide (NADH)
methemoglobin reductase deficient individuals.
Cardiac: Cardiac Arrhythmia and QT interval prolongation (see PRECAUTIONS, OVERDOSAGE).
Nervous Sys tem: Dizziness.
Skin and Soft Tis s ue: Rash, pruritus.

OVERDOSAGE
Symptoms of overdosage of primaquine phosphate include abdominal cramps, vomiting, burning
epigastric distress, central nervous system and cardiovascular disturbances, including cardiac
arrhythmia and QT interval prolongation, cyanosis, methemoglobinemia, moderate leukocytosis or
leukopenia, and anemia in G6PD deficient patients. The most striking symptoms are granulocytopenia
and acute hemolytic anemia in sensitive persons. Acute hemolysis occurs, but patients recover
completely if the dosage is discontinued.

DOSAGE AND ADMINISTRATION

Primaquine phosphate is recommended only for the radical cure of vivax malaria, the prevention of
relapse in vivax malaria, or following the termination of chloroquine phosphate suppressive therapy in
an area where vivax malaria is endemic. Patients suffering from an attack of vivax malaria or having
parasitized red blood cells should receive a course of chloroquine phosphate, which quickly destroys
the erythrocytic parasites and terminates the paroxysm. Primaquine phosphate should be administered
concurrently in order to eradicate the exoerythrocytic parasites in a dosage of 1 tablet (equivalent to 15
mg base) daily for 14 days.
HOW SUPPLIED
Primaquine Phosphate USP Tablets are solid oral formulation round tablet debossed "BY4" available in
26.3 mg and 100 count.
Available in bottles of 100. (NDC 76385-102-02)
Store at controlled room temperature: 25°C (77°F); excursions are permitted to 15°-30°C (59°-86°F)
[see USP Controlled Room Temperature].
Dispense in tight, light-resistant container as defined in the USP/NF.

Clinical Studies
Persons with acute attacks of vivax malaria, provoked by the release of erythrocytic forms of the
parasite, respond readily to therapy, particularly to Chloroquine Phosphate. Primaquine eliminates
tissue (exoerythrocytic) infection and prevents relapses in experimentally induced vivax malaria in
human volunteers and in persons with naturally occurring infections and is a valuable adjunct to
conventional therapy in vivax malaria.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA1088.

REFERENCES
1. Shubber EK, Jacobson-Kram D, Williams JR. Comparison of the Ames assay and the induction of
sister chromatid exchanges: results with ten pharmaceuticals and five selected agents. Cell Biol
Toxicol.1986; 2:379-99.
2. Chatterjee T, Muhkopadhyay A, Khan KA, Giri AK. Comparative mutagenic and genotoxic effects
of three antimalarial drugs, chloroquine, primaquine and amodiaquine. Mutagenesis. 1998;13:619-
24.
3. Marss TC. Bright JE, Morris BC. Methemoglobinogenic potential of primaquine and its
mutagenicity in the Ames test. Toxicol Lett. 1987; 36:281-7.
4. Ono T, Norimatsu M, Yoshimura H. Mutagenic evaluation of primaquine, pentaquine and pamaquine
in the Salmonella/mammalian microsome assay. Mutat Res. 1994; 325:7-10.
5. Giovanella F, Ferreira GK, de Prá1 SDT, Carvalho-SilvaM, GomesLM, Scaini G, Goncalves RC4,
Michels M, Galant LS, Longaretti LM, Dajori AL, AndradeVM, DalPizzol F, Streck EL, de Souza
RP. Effects of primaquine and chloroquine on oxidative stress parameters in rats. Anais da
Academia Brasileira de Ciencias (Annals of the Brazilian Academy of Sciences). 2015; 87: 1487-
1496.
6. Trutter JA, Reno FE, Durloo RS. Teratogenicity studies wrth a candidate antileishmanial drug. The
Toxicologist. 1983; 3:65.
7. Beveridge E, Caldwell IC, Latter VS, Neal RA, Udall V, Waldron MM. The activity against
Trypanosoma cruzi and cutaneous leishmaniasis, and toxicity, of moxipraquine (349C59). Trans R
Soc Trop Med Hyg. 1980; 74:43-51.

Rx Only
Manufactured for:
Bayshore Pharmaceuticals LLC
Short Hills, NJ 07078
1-800-593-5725
Revised 11/2017
PRINCIPAL DISPLAY PANEL - 26.3 mg Tablet Bottle Label
NDC 76385-102-01
Primaquine phos phate Tablets , USP
26.3 mg (=15 mg bas e)
Rx only
100 Tablets
Adult dosage should not exceed 1 tablet daily for 14 days.
Discontinue promptly if signs suggestive of hemolytic anemia occur (i.e., darkening of urine, marked
fall of hemoglobin, or erythrocyte count). Usual Dosage: See package insert.
Dispense in tight, light-resistant container as defined in the USP/NF. Store at 25° C (77° F); excursions
permitted to 15° C-30° C (59° F-86° F) [see USP Controlled Room Temperature].
Manufactured for: Bayshore Pharmaceuticals LLC
Short Hills, NJ 07078

PRIMAQUINE PHOSPHATE
primaquine phosphate tablet
Product Information
Prod uct T yp e HUMAN PRESCRIPTIO N DRUG Ite m Cod e (S ource ) NDC:76 38 5-10 2

Route of Ad minis tration O RAL

Active Ing redient/Active Moiety

Ing redient Name Basis o f Streng th Streng th
Prima quine Pho spha te (UNII: H0 9 8 2HF78 B) (prima quine - UNII:MVR36 34GX1) prima quine 15 mg

Inactive Ing redients

Ing redient Name Streng th
CELLULO SE, MICRO CRYSTALLINE (UNII: O P1R32D6 1U)
STARCH, CO RN (UNII: O 8 232NY3SJ)
LACTO SE MO NO HYDRATE (UNII: EWQ 57Q 8 I5X)
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
WATER (UNII: 0 59 Q F0 KO 0 R)
HYPRO MELLO SES (UNII: 3NXW29 V3WO )
TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)
PO LYETHYLENE GLYCO LS (UNII: 3WJQ 0 SDW1A)
FD&C RED NO . 4 0 (UNII: WZB9 127XO A)
FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQ K)

Product Characteristics
Color PURPLE S core no sc o re
S hap e RO UND S iz e 8 mm
Flavor Imp rint Cod e BY4
Contains

Packag ing
# Item Co de Packag e Descriptio n Marketing Start Date Marketing End Date
1 NDC:76 38 5-10 2-0 1 10 0 in 1 BO TTLE; Type 0 : No t a Co mbina tio n Pro duc t 0 8 /0 1/20 14

Marketing Information
Marke ting Cate gory Ap p lication Numb e r or Monograp h Citation Marke ting S tart Date Marke ting End Date
ANDA ANDA20 4476 0 8 /0 1/20 14

Labeler - Bays hore Pharmaceuticals , LLC (968737416)

Registrant - Bays hore Pharmaceuticals , LLC (968737416)

Establishment
 Name Ad d re s s ID/FEI Bus ine s s Op e rations
Ce ro ve ne , Inc 79 0 38 79 27 ma nufa c ture (76 38 5-10 2)

Revised: 1/2018 Bayshore Pharmaceuticals, LLC