Pregnancy Multivitamin Product Monograph

INDICATIONS AND CLINICAL USE

Pregnancy Multivitamin is a vitamin-mineral supplement specially formulated for use in women at least 2-3 months prior to conception⁴, throughout pregnancy and during the postnatal period.

Women who have poor folate status from multifactorial dietary and environmental conditions, including poor eating habits, stringent dieting for weight loss, drug and alcohol abuse, and cigarette smoking should discuss folate supplementation with their physician.^{7, 8}

Oral contraceptive users may also have lower folate concentrations than non-users as estrogen and progesterone could lower plasma and erythrocyte folate levels. Supplementation with folic acid may theoretically reduce the occurrence of maternal folic acid deficiency.

The physiological changes of pregnancy call for extra nutrients and energy to meet demands of expanding blood supply, growth of maternal tissues, developing fetus, loss of maternal tissues at birth, and preparation for lactation. During pregnancy, special attention should be given to folate, calcium, vitamin D and iron intakes because there is a potential for inadequate intakes in some groups of women.

Taking vitamin and mineral supplements does not eliminate the need for balanced nutrition.

Pregnancy Multivitamin is formulated as two tablets in order to optimize the absorption of iron, calcium and folic acid; one pink (a.m.) tablet (with iron) is to be taken in the morning and a distinctly different blue (p.m.) tablet (with calcium and folic acid) is to be taken in the evening. The rationale for this two tablet approach is to enhance bioavailability of iron; adjust the iron content so that it reduces adverse effects such as nausea, constipation, fatigue, diarrhea and headache associated with supplements containing higher levels of iron (60 mg) and; therefore increase compliance to Pregnancy Multivitamin. Calcium is provided separately from iron to avoid calcium inhibition of iron absorption from the gastrointestinal tract.^{1, 2} A higher dose of vitamin C is also present in the morning tablet to facilitate iron absorption.^{9, 10} Manganese was purposely excluded from these tablets so as not to affect iron absorption.^{9, 11}

Concurrent ingestion of folic acid and iron may result in the formation of stable complexes.³ Folic acid is provided separately from iron to prevent their decreased intestinal absorption.

CONTRAINDICATIONS

These products are contraindicated in patients with known hypersensitivity to any of the ingredients in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

Although it has been suggested that high doses of folate may mask manifestations of vitamin B₁₂ deficiency, a study by Metz et al. (2004) could not demonstrate that high serum folate levels masked the macrocytosis of cobalamin deficiency whether the serum folate was low, normal or high.¹²

To address potential concerns regarding the masking of vitamin B₁₂ deficiency and the potential precipitation or exacerbation of the progression of neurological complications associated with vitamin B₁₂ deficiency, the use of folic acid in conjunction with vitamin B₁₂ as a supplement should be recommended.¹³ Vitamin B₁₂ levels may be monitored if, in the opinion of the healthcare professional, it is warranted.

Keep this product out of the reach of children. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. In case of accidental overdose, call a regional poison control centre immediately (See OVERDOSAGE).

Do not exceed the recommended dose.

Dependence/Tolerance

There is no information to indicate that abuse or dependency occurs at the concentration of vitamins and minerals found in vitamin-mineral supplement tablets for prenatal/postpartum use.

Hematologic

Folic acid should be used in conjunction with vitamin B₁₂ in order to avoid potential neurologic complications. Any dose of folic acid over 1 mg per day may require monitoring for vitamin B₁₂ deficiency by a healthcare provider.

Neurologic

Women with seizure disorders controlled on anticonvulsant medications (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproic acid) may have exacerbation of seizures when folic acid is taken.^{4, 26, 30}

Special Populations

Pregnant Women:

Although the use of a folic acid supplement during the periconceptional period reduces the number of NTDs, they cannot be completely avoided through folate supplementation due to their multifactorial origin.

Taking vitamin and mineral supplements does not eliminate the need for balanced nutrition.

Baseline Risk:

The background baseline risk of major malformations for all pregnancies is approximately 1-3%. This is the risk of having a child with a birth defect when no teratogenic exposure occurs in pregnancy. This underlying risk may be increased due to maternal age, medical or family history, or exposures to certain drugs, chemicals or levels of radiation known to cause birth defects.

Each year, a quarter of a million pregnancies worldwide result in the birth of an infant with a neural tube defect (NTD) or an abortion performed because of such defect.⁸ In a recent study, a total of 2446 subjects with NTDs were recorded among 1.9 million births from 1993 to 2002 in seven Canadian provinces. The prevalence of NTDs was 0.86 per 1000 births.¹⁴

Nursing Women:

Pregnancy Multivitamin is specifically indicated in the postpartum period.

The passage of vitamins and minerals into breast milk can be expected. Folic acid is actively excreted into breast milk. Accumulation of folate in milk takes precedence over maternal folate needs. Levels of folic acid are relatively low in colostrum but as lactation proceeds, concentrations of the vitamin rise.

Folate levels in newborns and breast-fed infants are consistently higher than those in mothers and normal adults. In Japanese mothers, mean breast milk folate concentrations were 141.4 ng/mL, resulting in a total intake by the infant of 14-25 mcg/kg/day. Much lower mean levels were measured in pooled human milk in an English study examining preterm (26 mothers, 29-34 weeks) and term (35 mothers, 39 weeks or longer) patients. Preterm milk folate concentrations rose from 10.6 ng/mL (colostrum) to 30.5 ng/mL post-natal (16-196 days), whereas term milk folate concentrations increased during the same period from 17.6 to 42.3 ng/mL.¹⁵

In one study, maternal serum and red blood cell folate levels increased significantly after 1 mg of folic acid/day for 4 weeks, but milk folate levels remained unchanged. Investigators gave well- nourished lactating women a multivitamin preparation containing 0.8 mg of folic acid. At 6 months postpartum, milk concentrations of folate did not differ significantly from those of

controls who were not receiving supplements. Other investigators measured more than adequate blood folate levels in American breast-fed infants during the 1^st year of life. The mean milk concentration of folate consumed by these infants was 85 ng/mL.¹⁵

In a study of lactating mothers with megaloblastic anemia treated with 5 mg/day of folic acid for 3 days, breast milk folate rose from 7-9 ng/mL to 15-40 ng/mL 1 day after treatment began. The elevated levels were maintained for 3 weeks without further treatment. Nine lower- socioeconomic status women were treated with multivitamins containing 0.8 mg of folic acid and were compared with seven untreated controls. Breast milk folate was significantly higher in the treated women. In another study of lactating women with low nutritional status, supplementation with folic acid, 0.2-10.0 mg/day, resulted in mean milk concentrations of 2.3-5.6 ng/mL. Milk concentrations were directly proportional to dietary intake.¹⁵

Monitoring and Laboratory Tests

To address potential concerns that high doses of folate may mask manifestations of vitamin B₁₂ deficiency, signs or symptoms of vitamin B₁₂ deficiency should be considered before initiating folic acid supplementation if doses are greater than 1.0 mg. Vitamin B₁₂ levels may be monitored before and during Pregnancy Multivitamin therapy if in the opinion of the healthcare professional it is warranted.

Monitor folate level when drugs known to interact with folic acid are taken concomitantly (See Table 2, DRUG INTERACTIONS).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Allergic sensitization has been reported following both oral and parenteral administration of folic acid.

At high doses (e.g. 15 mg/day) folic acid has been associated on rare occasion with various gastrointestinal symptoms and CNS effects such as sleep disturbances, difficulty concentrating, irritability, hyperactivity, excitement, mental depression, confusion, and impaired judgment.¹⁶ In general, adverse reactions associated with iron supplements whether alone or in a multivitamin are: constipation, nausea, fatigue, diarrhea and headache.^{17, 18, 19}

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

A randomized, crossover open labelled study in 138 pregnant women attending outpatient clinics was conducted to compare tolerability and compliance with vitamin-mineral supplement tablets for prenatal/postpartum use (a.m. and p.m. tablets) versus a supplement with high iron content in pregnant women.²⁰ An equal number of pregnant women suffering from nausea and vomiting of pregnancy (NVP) and pregnant women without NVP were randomized to receive either vitamin-mineral supplement tablets for prenatal/postpartum use or a supplement with high iron content for one month. The primary end point of interest was the mean rate of adverse events including decreased compliance. The mean rate of adverse events was collected for nausea, constipation and other adverse drug events and is illustrated in Table 2. Incidence of nausea was approximately 9% in vitamin-mineral supplement tablets for prenatal/postpartum use group versus 10% in the supplement with high iron content group (p=0.71); incidence of constipation was 22.5% in vitamin-mineral supplement tablets for prenatal/postpartum use group versus 34.8% in the supplement with high iron content group (p=0.03) and for other adverse events, the average number of events was 10.4 for the vitamin-mineral supplement tablets for prenatal/postpartum use group versus 9.9 for the supplement with high iron content group (p=0.95).²⁰

Table 2 - Overall Study Results, Comparing vitamin-mineral supplement tablets for prenatal/postpartum use (Low Iron) to a Supplement with a High Iron Content over a Month Administration in a Cross-Over Design.

In a single-dose crossover pharmacokinetic study conducted with the vitamin-mineral supplement tablets for prenatal/postpartum use (p.m.) tablet in 6 healthy non-pregnant women (18-45 years), no adverse reactions were reported.²¹

In another study of similar design, 12 healthy women were administered high iron and calcium and low iron without calcium [vitamin-mineral supplement tablets for prenatal/postpartum use pink (a.m.) tablet] separately on two different occasions. No adverse reactions were reported.⁹

Abnormal Hematologic and Clinical Chemistry Findings

None reported.

Post-Market Adverse Drug Reactions

Pregnancy Multivitamin and Pregnancy Multivitamin Folic 5have the same medicinal ingredients and strengths with the exception of the amount of folic acid (1.1 mg vs. 5 mg). Spontaneous adverse reactions reported for these products are summarized in Table 3.^{22, 23} Reactions are presented by MedDRA System Organ Class (SOC) and Preferred Terms (signs, symptoms and diagnosis) from spontaneous notification.

Table 3 - Cumulative Summary of Adverse Reactions from Post-Marketing Spontaneous Reporting Systems for vitamin-mineral supplement tablets for prenatal/postpartum use and vitamin-mineral supplement tablets high dose folic acid for prenatal use (5 mg) as of September 30, 2008.

DRUG INTERACTIONS

Overview

No formal vitamin/mineral-drug interaction studies have been performed with vitamin-mineral supplement tablets for prenatal/postpartum use.

Iron supplements may decrease absorption of thyroid hormone medications.²⁴ Therefore, iron supplements whether alone or as part of a prenatal supplement, should not be taken at the same time as levothyroxine or other thyroid hormone medications (Synthroid^®, Eltroxin^®, Levo-T^®, Levothroid^®, Levoxyl^®, Euthroid^®, Thyrolar^®, etc.). Allow at least four (4) hours between taking iron and thyroid hormones.²⁴ Calcium can also interfere with the absorption of thyroid drugs.²⁴ Allow at least four (4) hours between taking calcium and thyroid hormones.

Due to the inhibitory effect of calcium on iron absorption, women should be encouraged to take these supplements at different time. A high intake of iron can interfere with zinc absorption therefore; 15 mg of supplemental zinc should be taken when elemental iron supplementation exceeds 30 mg per day. When supplemental zinc is taken, concurrent supplementation with

2 mg copper is advised.²⁵

Concurrent ingestion of folic acid and iron may result in the formation of stable complexes with iron, resulting in their decreased intestinal absorption.³

Several other drugs have reduced bioavailability when ingested with iron preparations. These include carbidopa, ciprofloxacin, levodopa, methyldopa, penicillamine, and tetracyclines.³ A large number of drugs form stable complexes with iron, however, little is known about the clinical consequences of this binding. Further investigation is required to determine the clinical interactions between iron and drug molecules.

Drugs including, antibiotic therapies, bisphosphonates, carbidopa, fluoroquinolone antibiotics, levodopa, methyldopa and penicillamine should be taken at least two (2) hours apart from Pregnancy Multivitamin.

Drugs including, cholestyramine, colestipol, levothyroxine and mycophenolate mofetil should be taken at least four (4) hours apart from Pregnancy Multivitamin.

Vitamin/Mineral-Drug Interactions

Table 4 - Vitamin/Mineral- Drug Interactions for Pregnancy Multivitamin

Vitamin/Mineral-Food Interactions

Interactions with food have been established with iron and calcium.

Iron

Factors that enhance non-heme iron absorption include: meat, poultry, fish and vitamin C.¹ Factors that inhibit non-heme iron absorption include: polyphenols in tea, coffee; phytate in legumes, soybeans, whole grains; oxalate in spinach, chard, beet greens, rhubarb, sweet potato and calcium in both food and supplements.¹

Due to the inhibitory effect of calcium on iron absorption, women should be encouraged to take these supplements at different times.¹

Calcium

Compounds such as oxalate and phytate reduce calcium absorption.¹ These compounds are found in foods such as legumes, grains, spinach, chard, beet greens, sweet potatoes and rhubarb.

Absorption of calcium carbonate can be improved when food has increased gastric acid levels.²

Vitamin/Mineral-Vitamin/Mineral interactions

Vitamin/mineral-vitamin/mineral interactions are important for the Pregnancy Multivitamin formulation, the dosing regimen itself [pink a.m. and blue p.m. tablets at least four (4) hours apart] as well as the timing of administration of external sources of vitamins and minerals.

Concurrent ingestion of folic acid and iron may result in the formation of stable complexes with iron, decreasing their intestinal absorption.³ Vitamin C is known to increase the absorption of iron.^{9, 10} Calcium has an inhibitory effect on iron absorption. Manganese also interferes with iron absorption.^{9, 11} Vitamin D metabolites enhance calcium absorption.²

These same interactions are seen with external sources of vitamins and minerals including supplements.

High intake of iron can interfere with zinc absorption. For this reason, 15 mg per day supplemental zinc should be taken when elemental iron supplementation exceeds 30 mg per day. When supplemental zinc is taken, concurrent supplementation with 2 mg copper is advised.²⁵

Table 5 - Vitamin/Mineral - Vitamin/Mineral Interactions for Pregnancy Multivitamin

Vitamin/Mineral-Herb Interactions

Interactions with herbal products have not been established.

Vitamin/Mineral-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

For Pregnancy Multivitamin take one pink (a.m.) tablet in the morning and one blue (p.m.) tablet in the evening at least four (4) hours apart. The purpose of taking the two tablets at different times is to prevent calcium inhibition on the absorption of iron^{1, 2} and to prevent folic acid from interacting with iron resulting in their decreased intestinal absorption.³

For Pregnancy Multivitamin, take at least 2-3 months prior to conception,⁴ throughout pregnancy and during the postnatal period.

It is preferable to take the Pregnancy Multivitamin pink (a.m.) tablet on an empty stomach with a glass of water and to wait at least one (1) hour before taking any food to optimize iron absorption, and to take the Pregnancy Multivitamin blue (p.m.) tablet close to the evening meal (before or after), i.e. within one (1) hour of the evening meal, to optimize calcium absorption.

The schedule may be individualized according to a woman’s specific condition:

• For women taking calcium rich food for breakfast, the Pregnancy Multivitamin pink (a.m.) tablet may be taken two (2) hours or more after breakfast. Following administration of the pink (a.m.) tablet a wait of one (1) additional hour is recommended before eating in order to optimize the absorption of iron.
• For women suffering from nausea and/or vomiting in the morning where it is difficult to take vitamin-mineral supplements on an empty stomach, the Pregnancy Multivitamin pink (a.m.) tablet may be taken two (2) hours or more after breakfast. Following administration of the pink (a.m.) tablet a wait of one (1) additional hour is recommended before eating in order to optimize the absorption of iron.
• For women taking levothyroxine hormone in the morning, it is recommended to take the Pregnancy Multivitamin pink (a.m.) tablet at least four (4) hours apart to optimize the absorption of levothyroxine hormone. For women taking levothyroxine hormone at bedtime, it is recommended to take the Pregnancy Multivitamin blue (p.m.) tablet at least four (4) hours apart to optimize the absorption of levothyroxine hormone.

There is no specific recommendation to support a different dosage of vitamin-mineral supplement in multiple pregnancies.

Missed Dose

When a dose has been missed, it should be taken as soon as possible: one pink (a.m.) and one blue (p.m.) tablet should be taken within a 24 hour period. It is recommended that Pregnancy Multivitamin pink (a.m.) and blue (p.m.) tablets be taken at least four (4) hours apart in order to optimize the absorption of nutrients.

The prescribed dosing schedule should then continue as directed by physician or healthcare professional.

Administration

Pregnancy Multivitamin tablets are to be taken orally.

Tablets are not intended to be crushed, chewed or split. No stability and absorption data is available for crushed, chewed or split vitamin-mineral supplement tablets for prenatal/postpartum use.

OVERDOSAGE

Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6.

Pregnancy Multivitamin are supplied in a 30-day blister pack containing 30 oval, pink (a.m.) tablets and 30 oval, blue (p.m.) tablets. Each Pregnancy Multivitamin pink (a.m.) tablet contains 35 mg of elemental iron. No iron is contained in the Pregnancy Multivitamin blue (p.m.) tablet. The amount of elemental iron in one box or a 30-day supply of Pregnancy Multivitamin is 1050 mg.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Pregnancy Multivitamin provide a supplement of vitamins and minerals in an immediate release dosage form. Administration of the pink (a.m.) and the blue (p.m.) tablets at two different times helps to maximize the absorption of iron, calcium and folic acid.

Clinical Pharmacology

Folic acid, also known as folate, pteroylglutamic acid or vitamin B₉, is a water-soluble B complex vitamin. After absorption from the gastrointestinal tract, folic acid is converted in the liver to tetrahydrofolic acid, which is a cofactor in the biosynthesis of purines and thymidylates of nucleic acids. An exogenous source of folic acid is necessary for the synthesis of nucleoproteins and maintenance of normal erythropoiesis. There is strong evidence that prophylactic therapy with folic acid, prior to and during pregnancy, can reduce the risk of fetal neural tube defects (NTDs). NTDs result from improper development and closure of the neural tube during the third and fourth weeks of gestation. Pregnancies affected by an NTD may result in a miscarriage or stillbirth, and children born with an NTD may have mild to severe disability or die in early childhood. NTDs include spina bifida, anencephaly and encephalocele.

Although the use of a folic acid supplement during the periconceptional period reduces the number of NTDs, they cannot be completely avoided through folate supplementation because of their multifactorial origin. For women who had prior history of NTDs, the recurrence rate is

2-3%. Consuming 5 mg of folic acid daily has the potential of reducing the incidence of another NTD pregnancy by up to 72%, i.e., down to 1%.

There is evidence that an increase of 0.4 mg/day of folic acid would reduce the risk of neural tube defects for all women planning a pregnancy by about 36%, 1 mg per day would reduce the risk by about 57%, 1.1 mg per day would reduce the risk by about 59% and the use of a 5 mg tablet daily would reduce the risk by about 85%.⁸

For management of a suspected drug overdose, contact your regional poison control centre.

Pharmacokinetics

The absorption of iron following the administration of vitamin-mineral supplement tablets for prenatal/postpartum use / vitamin-mineral supplement tablets high dose folic acid for prenatal use pink (a.m.) tablets was measured in twelve healthy, non-pregnant women. The area under the concentration- time curve (AUC) for serum iron was 79.1 ± 36.0 mcM·h. Upon standardizing the AUC for dose, the relative absorption over the 8-hour time period was 2.3 ± 1.0 mcM·h/mg.⁹

There is no evidence of circadian rhythm variation in folate pharmacokinetics. In a crossover design, six healthy, non-pregnant women were randomized to receive vitamin-mineral supplement tablets for prenatal/postpartum use blue (p.m.), containing 1.1 mg of folic acid, in the morning or evening.²¹ Serum folate levels were measured over 10 hours. The area under the concentration-time curve (AUC) was used to compare the extent of absorption between the two time periods. The mean AUC values for serum folate after administration of the vitamin-mineral supplement tablets for prenatal/postpartum use blue (p.m.) were 334.5 ± 119.6 nM·h and 283.1 ± 64.3 nM·h for morning and evening, respectively (p=0.17). The morning and evening peak serum folate concentrations (C_max) were also similar (135.3 ± 41.7 nM and 130.3 ± 14.2 nM, respectively) (p=0.75). There was no difference in the time to peak concentration (T_max) for the morning (1 ± 0.5 hour) and the evening (1 ± 0.4 hour) administration. Folic acid contained in the vitamin-mineral supplement tablets for prenatal/postpartum use blue (p.m.) was absorbed similarly whether administered in the morning or in the evening.

A study comparing folic acid pharmacokinetics was completed where serum folate levels of single dose vitamin-mineral supplement tablets for prenatal/postpartum use and vitamin-mineral supplement tablets high dose folic acid for prenatal use were measured pre-dose and up to 10 hours post dose in healthy non-pregnant fertile women between the ages of 18 and 45 years. The mean area under the curve (AUC) of 1.1 mg and 5 mg folic acid were 147.6 ± 52.8 (ng/mL)∙hr and 997.5 ± 271.9 (ng/mL)∙hr, respectively (p<0.0002). An approximate 5-fold difference was detected in the peak concentrations (C_max) between the 2 groups (p<0.0005), alongside a slight difference in the times to peak (T_max) (p=0.02). The estimated steady-state serum folate concentrations produced by 1.1 mg and 5 mg folic acid were 6.2 ± 2.2 ng/mL and 41.6 ± 11.3 ng/mL, respectively (p<0.0002), prior to its summation with initial (baseline) steady-state levels. Single dose administration between 1.1 mg and 5 mg folic acid demonstrated linear pharmacokinetics, with approximately a 5-fold difference between the 2 doses in serum folate contribution to steady-state levels, under ideal adherence.³²

The study results are summarized in Table 6 below:

Table 6 - Single Dose Pharmacokinetic Comparison of vitamin-mineral supplement tablets high dose folic acid for prenatal use (5 mg) versus vitamin-mineral supplement tablets for prenatal/postpartum use (1.1 mg) Folic Acid Ingestion, Among Non-Pregnant Women of Childbearing Age

Note: Data presented as mean ± standard deviation

^¶ Overall estimated steady-state serum folate concentration = baseline concentration + estimated steady-state serum folate concentration produced by supplemental folic acid.

Special Populations and Conditions

Race: No data is available on differences in the pharmacokinetics of either vitamin-mineral supplement tablets for prenatal/postpartum use pink (a.m.) or blue (p.m.) tablet in different races.

Hepatic Insufficiency: No data is available on differences in the pharmacokinetics of either vitamin-mineral supplement tablets for prenatal/postpartum use pink (a.m.) or blue (p.m.) tablet in patients with hepatic insufficiency.

Renal Insufficiency: No data is available on differences in the pharmacokinetics of either vitamin-mineral supplement tablets for prenatal/postpartum use pink (a.m.) or blue (p.m.) tablet in renal insufficiency.

Genetic Polymorphism: No data is available on differences in the pharmacokinetics of either vitamin-mineral supplement tablets for prenatal/postpartum use pink (a.m.) or blue (p.m.) tablet in patients with genetic polymorphism.

STORAGE AND STABILITY

Store at room temperature (15 to 30ºC).

Protect from moisture. Contact with moisture may produce surface discoloration or erosion of the tablet.

Keep out of reach and sight of children.

SPECIAL HANDLING INSTRUCTIONS

No special handling instructions are required.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Pregnancy Multivitamin are supplied in a 30-day blister pack containing 30 oval, pink (a.m.) tablets and 30 oval, blue (p.m.) tablets.

Medicinal Ingredients:

Each oval shaped, pink (a.m.), film-coated, immediate release tablet contains:

• * Elemental amount

^† The quantity of vitamin E is expressed as milligrams (mg) of RRR-α-tocopherol (AT).

Each oval shaped, blue/ (p.m.), film coated, immediate release tablet contains:

• * Elemental amount

Non-medicinal Ingredients (organized alphabetically):

Pregnancy Multivitamin pink (a.m.) tablets are pink, oval shaped, biconvex, film coated tablets with “D” engraved on both sides and contains the following non-medicinal ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, FD&C Blue No. 1, FD&C Red No. 40, glucose syrup, hydroxy propyl methyl cellulose, microcrystalline cellulose, modified food starch, polyvinyl alcohol, povidone, polyethylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talcum, titanium dioxide.

Pregnancy Multivitamin blue (p.m.) tablets light blue, oval shaped, biconvex, film coated tablets with “N” engraved on both sides and contains the following non-medicinal ingredients: citric acid, croscarmellose sodium, FD&C Red No. 40, FD&C Blue No. 2, magnesium stearate, maltodextrin, pregelatinised starch, polyvinyl alcohol, sodium ascorbate, sodium citrate, sucrose, talcum, titanium dioxide, triacetin.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Folic acid

Chemical name: N-[4-[[(2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)-methyl]- amino]benzoyl]- L-glutamic Acid

Molecular formula and molecular mass: C₁₉H₁₉N₇O₆ 441.40 g/mol

Structural formula:

H

H N N N

2

N

N

O HN

O

H N

OH

O

O OH

Physicochemical properties: Yellow-orange crystalline powder. Soluble in water.

Insoluble in alcohol, ether, acetone.

Other Drug Substances:

CLINICAL TRIALS

Studies indicate that periconceptional use of supplements containing folic acid may substantially reduce the risk of occurrence (first affected pregnancy) and recurrence (additional affected pregnancies) of neural tube defects (NTDs).

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommend that women who could become pregnant be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily and that women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin dependent diabetes, epilepsy treatment with carbamazepine, phenobarbital, phenytoin, primidone or valproic acid) be advised that high-dose folic acid (4.0 mg–5.0 mg daily) supplementation is recommended.³⁰

Efficacy and safety of vitamin-mineral supplement tablets for prenatal/postpartum use and vitamin-mineral supplement tablets high dose folic acid for prenatal use formulations are supported by a large body of published literature addressing prenatal multivitamin-mineral supplementation in general and folic acid supplementation specifically.

A tolerability and compliance study was conducted with vitamin-mineral supplement tablets for prenatal/postpartum use versus a supplement with high iron content, in pregnant women. ²⁰ This randomized, crossover open labelled study was conducted in 138 pregnant women attending outpatient obstetric clinics in Ontario and Quebec. An equal number of women suffering from nausea and vomiting of pregnancy (NVP) and pregnant women without NVP were randomized to receive either vitamin-mineral supplement tablets for prenatal/postpartum use or a supplement with high iron content for one month. The women were instructed to keep a diary and record any adverse events, severity of their NVP, changes in their diet, use of medications and adherence to the study drug. One month later, the women were given the alternative product and asked to record the same information in the diary for the following month. The primary end point of interest was the mean rate of adverse events including decreased compliance.

A total of 138 patients completed the study and were included in the data analysis. There was a significantly higher incidence of reported constipation (34.8% for the supplement with high iron content versus 22.5% for vitamin-mineral supplement tablets for prenatal/postpartum use, p=0.03) and significantly longer duration of constipation (4.7% for the supplement with high iron content versus 3.1% for vitamin-mineral supplement tablets for prenatal/postpartum use, p=0.05) when taking a supplement with high iron content versus vitamin-mineral supplement tablets for prenatal/postpartum use. This suggests that pregnant women may experience less constipation when taking vitamin-mineral supplement tablets for prenatal/postpartum use. These results are attributed to the lower iron dose contained in vitamin-mineral supplement tablets for prenatal/postpartum use versus the supplement with a high iron content (35 mg versus 60 mg). Both products demonstrated similar compliance rates. However, it was found that non- compliance with the supplement with high iron content was related to the severity of nausea and vomiting of pregnancy. This may be explained by a substantially larger tablet size as compared to vitamin-mineral supplement tablets for prenatal/postpartum use and a direct effect of the higher iron content. Therefore, vitamin-mineral supplement tablets for prenatal/postpartum use may confer an advantage to women suffering from NVP due to higher tolerability as a result of lower iron content and smaller tablet size.

Additional data regarding the effect of folate and the associated risk reduction of NTDs have been derived from studies in literature. These studies are presented below in Table 7.

Table 7- Summary of Data from Literature Studies

REFERENCES

1. 1. PREGVIT and PREGVIT Folic 5 (vitamin-mineral supplement tablets for prenatal/postpartum use, folic acid 1.1 mg and folic acid 5 mg), control no #183056, Product Monograph, Duchesnay Inc (January 26, 2016).