Bonjesta- the first dual release combination of doxylamine-pyridoxine for morning sickness

Motherisk Intl J 2020;1;19

Bonjesta- the first dual release combination of doxylamine-pyridoxine for morning sickness

Gideon Koren, Rana Cohen, Adelson School of Medicine, Ariel University and Motherisk Israel Program

 

Question:

The delayed release of doxylamine/ pyridoxine (Diclegis®) works well in many of my patients with morning sickness. The problem I have is that it takes several hours to begin to work. Is there anything that can overcome this problem?

Answer:

Due to its delayed release properties, Diclegis® begins to exert its antiemetic properties 6-8 hours after ingestion, and hence symptom relief may be delayed and necessitate the use of an immediate release medication. In 2016 the FDA approved Bonjesta®, a novel, dual- release combination of doxylamine and pyridoxine, whereby a rapid release phase is followed by the delayed release drug, thus overcoming the time delay in action of Diclegis® .

 

 

Nausea and vomiting of pregnancy (NVP) affects up to 85 % of pregnant women. The term ‘‘morning sickness’’ commonly used for this condition is inappropriate as the symptoms of NVP can occur throughout the day and/or night [1]. Symptoms of NVP include nausea, gagging, retching and/or vomiting typically commencing between 4 and 9 weeks of pregnancy, peaking between 7 and 12 weeks and in the majority of  women subside between 12 and 16 weeks of pregnancy; however, in up to 15 %of women, symptoms continue till 20 weeks of gestation, and up to  10 % of women suffer throughout their entire pregnancy [2, 3].

The severity of NVP can range from mild to severe and it is best quantified by combining the degree of nausea, vomiting and retching (Table 1). The most severe form of NVP, hyperemesis gravidarum (HG), affects between 0.3–2 % of pregnancies and commonly requires hospitalization because of severe and persistent nausea and vomiting, weight loss of greater than 5 %, dehydration, electrolyte imbalances, and nutritional deficiencies [2–5].

 

Table1:

Women who have had NVP in a previous pregnancy are more likely to have recurrence of NVP in subsequent pregnancies. Repeated studies demonstrated that initiating antiemetic treatment prior to the first day of symptoms effectively lessen the severity of symptoms and reduce the recurrence of HG in women who experienced severe NVP in a previous pregnancy [6-7].

Management of NVP

Women with mild NVP often find lifestyle and dietary modifications to sufficiently manage  their  symptoms . Additionally, non-pharmacological interventions such as acupressure bands, acupuncture or ginger root powder capsules are often used ; however their reported  effectiveness has been inconsistent .

A relatively large number of antiemetic drugs have been proven effective in the treatment of nausea and vomiting caused by chemotherapy, motion sickness, GI conditions or cyclic vomiting [6]. However, their use in pregnancy is marred by lack of sufficient data on effectiveness and fetal safety [6-7] due mainly to the fears of drug companies and academia alike of studying medications in pregnancy.  The only drug approved and indicated for the treatment of NVP in the USA, Canada, Korea, Singapour  and some other countries is the delayed-release formulation of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride (HCl), after being  proven both effective and safe [8-12]. This combination was first introduced in the USA as Bendectin® in 1956. Initially, Bendectin® was formulated as a delayed-release combination of 10 mg doxylamine succinate, 10 mg pyridoxine, and 10 mg dicyclomine HCl [8, 13]. However, in 1976, an eight-way study of doxylamine, pyridoxine HCl, and dicyclomine showed that dicyclomine did not confer an independent antiemetic effect, and consequently, Bendectin® was reformulated to contain only 10 mg doxylamine succinate and 10 mg pyridoxine HCl [14-16].

The dose of the delayed-release doxylamine/pyridoxine for NVP is typically up to four tablets daily: two tablets at bedtime, one in the morning, and one in the mid-afternoon. This delayed-release formulation permits the antiemetic action to occur 4–6 h after ingestion; therefore, the bedtime dose would be effective in the early morning, the morning dose would be effective in the afternoon and the mid-afternoon dose would be effective in the evening, providing 24 h control of NVP symptoms [17,18]. It does have the shortcoming of lack of immediate effect, which was one of the reasons for the development of Bonjesta®.

 

  1. Pharmacology

3.1.Doxylamine Succinate

Doxylamine succinate (Fig. 1) is structurally related to histamine, antagonizing histamine’s effects on histamine 1 (H1) receptor sites; as a result, it possesses sedative effects. It is a member of the ethanolamine class of the first generation antihistamines. As with other members of this group, doxylamine possesses substantial antimuscarinic activity with low incidence of GI adverse effects . As with any other H1 blocker, doxylamine may exhibit anticholinergic effects if taken in large doses [19]. Doxylamine is well absorbed from the GI tract, with peak plasma concentrations achieved within 2–3 h, and the therapeutic effects usually persist for 4–6 h. Doxylamine is biotransformed in the liver by N-dealkylation to its principal metabolites N-desmethyl and N, N-didesmethyldoxylamine, which are excreted by the kidney [20]. Importantly, the delayed-release formulation of Diclegis®/ Diclectin® tablets has different pharmacokinetics, which will be discussed below.

 

Pyridoxine Hydrochloride

Pyridoxine HCl (Fig. 1) is the usual form of vitamin B6   included in pharmaceutical products. Vitamin B6 is a collective name for pyridoxine, pyridoxal, and pyridoxamine, which are related natural compounds with similar biological properties [21]. Pyridoxine is readily absorbed from the GI tract, mainly in the jejunum. The drug is primarily metabolized in the liver to its four active metabolites pyridoxal, pyridoxal-5- phosphate (PLP), pyridoxamine, and pyridoxamine-5- phosphate. Following phosphorylation, its main metabolite, PLP, is released into the circulation and is highly protein bound. PLP is a cofactor in over 160 enzyme activities involved in a number of metabolic processes of amino acids, nucleic acids, unsaturated fatty acids, carbohydrates, glycogen, neurotransmitters, and porphyrin. The major metabolite 4-pyridoxic acid is inactive, and is excreted by the kidney [21]. A recent study has documented that PLP is the main antiemetic component of pyridoxine [22].

 

 

 

 Clinical Effectiveness of the Delayed-Release Combination of Doxylamine/Pyridoxine

The clinical effectiveness of the delayed-release combination of doxylamine and pyridoxine has been documented in a large number of randomized, controlled trials and open, controlled  post-marketing studies(Table 2 ).

Strong evidence supporting the effectiveness of this delayed-release combination was provided by population- based studies conducted in the USA and Canada [15]. The withdrawal of Bendectin® from the American and Canadian markets was temporally related to a two- to threefold increase in the rates of hospitalization of women for NVP [15]. These data suggest that the doxylamine/ pyridoxine combination is not only capable of eradicating mild and moderate forms of NVP, but also of preventing severe cases. Data from Neutel[23] reiterate these findings: the increased use of Diclectin® by Canadian women during the 1990s has been associated with a reduction in the hospitalization rate of women for severe NVP.

 

BONJESTA®:

Bonjesta®was approved by the FDA in November 2016 for the treatment of NVP when conservative management fails and it has been introduced to the American market in April 2018.[24]. The drive for the development of a novel, optimized reformulation of Diclegis® stemmed from  several objectives:

  • To combine a fast acting form of doxylamine/ pyridoxine with the delayed release form, thus conferring an immediate antiemetic effect which was not available with Diclegis®.
  • To decrease dosing from three times/day (morning, noon and evening) to twice a day, thus aiming to improve women’s adherence during the challenging days of nausea and vomiting symptomatology.
  • To decrease variability in serum concentrations of the active components of the medication.

Formulation and dose:

Bonjesta®, a faster acting, longer lasting optimized reformulation of Diclegis®, is a multilayer, extended-release tablet consisting of an enteric-coated core containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, and an immediate-release coating of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride, delivering a total of 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride(Figure 1).

 

Figure 1

The dual feature of Bonjesta® formulation allows for a rapid relief of NVP symptoms, and for sustained therapeutic effect, controlling nausea and vomiting symptoms that occur in the morning, throughout the day and into the night. The immediate-release portion in the coating layer allows for a fast rate of absorption and a rapid relief of NVP symptoms. Importantly, the absorption of the immediate-release portion of Bonjesta® is not affected by food. The immediate-release coating along with the delayed-release enteric-coated core make Bonjesta® an extended-release drug with a continuous pharmacodynamic effect.

The dose of each active ingredient in Bonjesta® tablets  is double that of the Diclegis® formulation, so the maximum daily recommended dosing is decreased from four tablets with Diclegis® to two tablets per day with Bonjesta® (i.e. one tablet in the morning and one tablet at bedtime), resulting in the same maximum daily dose as the Diclegis® formulation. Therefore, the formulation and schedule of administration of Bonjesta® reduces the pill burden and is likely to improve patient adherence. This is based on a secondary analysis of a double-blind randomized controlled trial conducted with the delayed-release combination of doxylamine succinate and pyridoxine hydrochloride (the same ingredients found in Bonjesta®), which demonstrated that the average number of tablets per day was negatively associated with adherence. This is clinically important especially for women who suffer from nausea and vomiting and have difficulties in swallowing tablets. In addition, by reducing the pill burden, improved patient adherence may reduce variations in the effective concentrations of doxylamine and pyridoxal 5’-phosphate plasma, ensuring that Bonjesta® provides sustained therapeutic effect.

Bonjesta® should be taken as a daily prescription, and not on an as-needed basis, in order to achieve therapeutic steady-state concentrations of the active ingredients for optimal anti-nauseant and anti-emetic effects.1 After administration of Bonjesta®, due to its immediate-release portion, there is a rapid onset of action followed by the delayed-release action. The dosing regimen begins with one tablet taken at bedtime (Day 1). If NVP symptoms persist on Day 2, a second tablet is to be added in the morning to control NVP symptoms throughout the day. Hence, the maximum recommended dose is two tablets per day, one in the morning and one at bedtime .

 

The Pharmacokinetic Novelty  of Bonjesta® 

For the purpose of development of Bonjesta® the pharmacokinetics of doxylamine succinate and pyridoxine hydrochloride were studied exclusively in healthy adult females to ensure that they relate directly to women of reproductive age.

 

Figure 2 :

In a single-dose, crossover study conducted in 48 healthy, premenopausal women under fasting conditions, one Bonjesta® (20 mg doxylamine succinate and 20 mg pyridoxine) tablet was bioequivalent to two combination tablets of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride based on systemic  exposure (AUC) and peak concentrations (Cmax) of doxylamine and baseline corrected pyridoxal 5′-phosphate.  Mean ± SD plasma (whole blood for pyridoxal) pharmacokinetic parameters are summarized in Table 2.

Table 2. Single-Dose Pharmacokinetic Parameters of Bonjesta® in healthy premenopausal, non-pregnant adult women

 

 

  BONJESTA

Mean ± SD

AUC0-t
(ng•h/mL)
AUC0-inf
(ng•h/mL)
AUC0-72
(ng•h/mL)
Cmax
(ng/mL)
Tmaxb
(h)
Doxylamine N=48 1367.0 ± 356.7 1425.8 ± 405.1 --- 92.3 ± 15.7  4.5
(2.5-5.5)
Pyridoxine N=47 42.3 ± 14.7 42.5 ± 14.7 --- 47.1 ± 18.7 0.5
(0.5-4.7)
Pyridoxala N=48* 203.7 ± 51.7 233.6 ± 55.9 --- 58.9 ± 17.0 3.0
(0.8-5.0)
Pyridoxal 5-phosphatea N=48 --- --- 1076.2 ± 382.2 30.1 ± 9.2 9.0
(3.0-16.0)

*N=46 for AUC0-inf

a Baseline corrected values

b Median (range)

 

In a multiple-dose, crossover clinical trial conducted in 31 healthy, premenopausal women, one Bonjesta® (20 mg doxylamine succinate and 20 mg pyridoxine) tablet given twice daily for 11 days was bioequivalent to one combination tablet of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride given three times daily (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime), based on the exposure (AUC) and peak concentration (Cmax) of doxylamine and baseline corrected pyridoxal 5’-phosphate. Mean ± SD plasma (whole blood for pyridoxal) PK parameters on day 11 are summarized in Table 3.

Table 3. Multiple-Dose Pharmacokinetic Parameters of Bonjesta® (given twice daily) in Healthy Premenopausal, Non-Pregnant Adult Women

 

  BONJESTA

Mean ± SD

AUC0-24 (ng•h/mL) AUC0-12

(ng•h/mL)

AUC0-6

(ng•h/mL)

Cmax

(ng/mL)

Tmax

(h)

Doxylamine N=34 2879.4 ±

696.0

1573.2 ±

406.5

883.6 ±

228.5

173.6 ±

45.5

3.5
(1.0-20.0)
Pyridoxine N=34 80.0 ±

22.7

46.3 ±

15.4

45.3 ±

16.3

48.2 ±

23.7

1.5
(0.3-16.5)
Pyridoxala N=34 1511.3 ±

300.0

848.1 ±

183.6

647.2 ±

149.6

189.6 ±

48.3

3.0
(2.0-15.0)
Pyridoxal 5-phosphatea N=34 1742.3 ±

554.3

831.7 ±

274.5

426.2 ±

144.0

85.9 ±

26.2

15.0
(2.0-24.0)

a Baseline corrected values

b Median (range)

 

In a single-dose, crossover clinical trial conducted in 23 healthy, premenopausal women, the administration of a high fat, high calorie meal delayed the absorption of doxylamine, pyridoxine, and pyridoxine metabolites. This delay was associated with lower peak concentrations of doxylamine, pyridoxine, and pyridoxal. The extent of absorption for pyridoxine was decreased (Table 4).

 

Table 4 – Mean ± SD Pharmacokinetic Parameters of Doxylamine and Pyridoxine Metabolites Following a Single Dose Administration of BONJESTA Under Fed and Fasted Conditions in Healthy Premenopausal Adult Women

 

 

  BONJESTA

N=23

AUC0-t (ng•h/mL) AUC0-inf (ng•h/mL) Cmax

(ng/mL)

Tmaxb,c

(h)

T1/2el

(h)

Doxylamine

Mean ± SD

Fasted 1273.7 ± 276.2 1321.9 ± 315.5 85.9±

10.6

3.5
(2.5-5.5)
11.9 ±

2.2

Fed 1242.8 ± 254.0 1281.4 ± 282.9 64.5 ± 15.2 6.5
(2.0 – 24.0)
12.7 ±

2.60

Pyridoxine

Mean ± SD

Fasted 34.7 ± 10.6 35.1 ±

8.5

38.9 ± 19.3 0.8
(0.3-4.3)
0.4 ±

0.2

Fed 22.8 ±

9.9

27.0 ± 10.1 12.7 ±

5.7

8.0
(1.0 – 21.0)
1.2 ±

2.4

Pyridoxala

Mean ± SD

Fasted 209.4 ± 30.0 244.0 ± 32.5 62.0 ±

17.8

2.3
(0.8-5.0)
8.0 ±

1.7

Fed 204.2 ± 25.7 249.2 ± 43.0 33.1 ± 6.1 6.0
(1.0-21.0)
12.5 ±

7.6

Pyridoxal 5′-phosphatea

Mean ± SD

Fasted 1021.7 ± 318.5 --- 27.4 ± 7.7 5.0
(3.0-71.8)
---
Fed 1064.6 ±

386.9

--- 30.2 ±

10.0

16.0
(6.0-22.0)
---

a Baseline corrected values

b Profile of Subject 20 was excluded

c Median (range)

 

 

The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxine metabolites such as pyridoxal, pyridoxamine, pyridoxal 5′-phosphate, and pyridoxamine 5′-phosphate also contribute to the biological antiemetic activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 67% and 37%, respectively, compared to fasting conditions. Similarly, food significantly reduces pyridoxal Cmax by approximately 46% compared to fasting conditions. In contrast, food did not affect pyridoxal 5′-phosphate Cmax and AUC.

The unique characteristics of Bonjesta with the early peak concentrations achieved by the immediate release coat, are shown in Figure 3.

 

Figure 3 : Mean (± SD) concentration-time profile for doxylamine (upper pannel) and pyridoxal 5’-phosphate (lower pannel) in the single-dose bioequivalence study, from a representative patient (red = Bonjesta®; blue = Diclegis®)

Compared to Diclegis®, Bonjesta® showed a faster onset of action (Tmax) for both doxylamine and  pyridoxal 5’-phosphate. This is due to the immediate-release portion in the coating of Bonjesta®, delivers parent drugs rapidly.

Based on the AUC0-t, AUC0-inf, and Cmax for doxylamine, and AUC0-72 and Cmax for baseline-corrected pyridoxal 5’-phosphate, this study met the bioequivalence criteria as all 90% geometric confidence intervals were within the acceptance range. Bonjesta® and Diclegis® had similar AUC and Cmax, therefore Bonjesta® can be considered as safe as Diclegis®.

 

Figure 4 : Mean (± SD) concentration-time profile for doxylamine (top) and pyridoxal 5’-phosphate (bottom) on Day 11 in the multiple-dose bioequivalence study (red = Bonjesta®; blue and green are the Diclegis® reference arms).

 

 

Compared to Diclegis®, Bonjesta® showed a faster onset of action (Tmax), even when the steady state has been reached. Indeed, median Tmax on Day 11 for doxylamine was 3.5 hours with Bonjesta®,  compared to 21 hours with Diclegis®. This is due to the immediate-release portion in the coating of Bonjesta®, that delivers parent drugs rapidly.

Based on the AUC0-24 and Cmax on Day 11 for doxylamine and baseline-corrected pyridoxal 5’-phosphate, this study met the bioequivalence criteria as all 90% geometric confidence intervals were within the acceptance range. Bonjesta® and Diclegis® had similar AUC and Cmax, profiles at steady state, therefore Bonjesta® can be considered as safe as Diclegis®.

 

 

The terminal elimination half-life of doxylamine and pyridoxine are 11.9 hours and 0.4 hours, respectively (Table 5).

 

Table 5 – Terminal elimination half-life (T½el) for Bonjesta  administered as a single dose under fasting conditions in healthy premenopausal adult Women (N=23)

 

BONJESTA T½el (h)
Doxylamine 11.9 ± 2.2
Pyridoxine 0.4 ± 0.2a
Pyridoxal 8.0 ± 1.7b

a N=12

b Baseline corrected value

 

 

Clinical Context of the Introduction of Bonjesta®

Bonjesta® is only the second FDA-approved medication indicated for the treatment of NVP when conservative management fails. The combination of doxylamine succinate and pyridoxine hydrochloride has been the subject of numerous clinical trials and epidemiological studies presented above.

Although other products, such as promethazine (formerly classified as Pregnancy Category C) metoclopramide  ondansetron (formerly classified as Pregnancy Category B), are currently used off-label for the management of NVP, none are specifically indicated for use in pregnancy. In fact, these products were developed for indications other than the treatment of NVP, and their respective prescribing information state that there are no adequate and well-controlled studies in pregnant women.[27,28]. [Table 6 ]

Moreover, although pyridoxine and doxylamine are available OTC in other products and have been used off-label for many years to treat NVP, potential disadvantages of using such generic preparations include the inconvenience of splitting tablets into appropriate doses, purchasing and using multiple products, identifying the correct version of product to use, and the lack of extended-release effects that allows for sustained control of NVP symptoms during the morning, and throughout the day and night. In example, only one out of the five versions of the sleep aid Unisom®, with similar-sounding names, contains doxylamine. The four other versions of this OTC brand use different ingredients, such as diphenhydramine, acetaminophen and melatonin, which make them prone to selection error. Evidence of such selection errors abound on numerous blogs and forums. In addition, these OTC products do not have the critical immediate action combined with delayed-release properties, nor are they labeled for use in pregnancy or indicated for the treatment of NVP, which may lead to confusion or concern.

 

Table 6. Pharmacological treatments for nausea and vomiting in pregnancy. Adapted from the Association of Professors of Gynecology and Obstetrics (APGO) Continuing Series on Women’s Health Education. Nausea and vomiting of pregnancy. APGO; February 2015.

 

Drug Pregnancy Category Recommended Dosing Regimen Comments
Doxylamine combined with pyridoxine A Up to 40 mg doxylamine and 40 mg pyridoxine daily.

Schedule and dose adjusted according to severity of symptoms.

 

Diclegis®(delayed-release combination of 10 mg doxylamine and 10 mg pyridoxine) and Bonjesta® (extended-release combination of 20 mg doxylamine and 20 mg pyridoxine) are the  only FDA-approved prescription treatment for NVP.
Dimenhydrinate B 50-100 mg Q 4-6 hours

up to 200 mg/day PO or PR

50 mg (in 50 mL saline, over 20 min) Q 4-6 hours IV

Considered as a second/third line therapy (as an add-on to doxylamine/pyridoxine) per SOGC and ACOG guidelines.
Promethazine C 12.5-25 mg Q 4-6 hours PO, PR, IM or IV Considered as a second/third line therapy (as an add-on to doxylamine/pyridoxine) per SOGC and ACOG guidelines.

Boxed warning for the injectable form of promethazine stating that perivascular extravasation, unintentional intra-arterial injection and intraneuronal or perineuronal infiltration of the drug may result in irritation and tissue damage, including gangrene, which, in turn, may result in amputation.

Chlorpromazine Not available 10-25 mg Q 4-6 hours PO or IM, or 50-100 mg Q 6-8 hours PR Considered as a second/third line therapy (as an add-on to doxylamine/pyridoxine) per SOGC and ACOG guidelines.

 

Metoclopramide B 5-10 mg Q 8 hours PO or IM Considered as a third/fourth line therapy (as an add-on to pyridoxine/doxylamine and dimenhydrinate or promethazine) per SOGC and ACOG guidelines.

Boxed warning for tardive dyskinesia, which is often irreversible. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose.

Prochlorperazine Not available 5-10 mg Q 6-8 hours PO, IM or IV Considered as a third/fourth line therapy (as an add-on to pyridoxine/doxylamine and dimenhydrinate or promethazine) per SOGC and ACOG guidelines.

 

Diphenhydramine B 25-50 mg Q 6 hours PO Considered as a second/third line therapy (as an add-on to doxylamine/pyridoxine) per SOGC guidelines.
Ondansetron B 4-8 mg Q 6-8 hours PO, or

8 mg over 15 min Q 12 hours IV or 1 mg/h IV continuously up to 24 hours

Considered as a second/third line therapy (as an add-on to doxylamine/pyridoxine) per SOGC and ACOG guidelines.

Recent data have observed an increased risk for cardiac defects and cleft palate after first trimester ondansetron use.

Boxed warning for QT prolongation and torsades de pointes, and potential risk for serotonin syndrome is still being assessed by the FDA.

Case series has suggested an association between ondansetron use and intestinal obstruction.

QHS-every night; QAM-every morning; QPM-every afternoon; Q-every; PO-per os (orally); PR-per rectum; IV-intravenous; IM-intramuscular

 

Conclusions

The combination of the immediate release with a delayed action is unique to Bonjesta® as it allows for the bedtime dose to be effective immediately and also provide with sustained control of NVP symptoms throughout the day. Pharmacokinetic studies have demonstrated the steady-state concentrations of the active ingredients and active metabolites after multiple dosing, and no other anti-emetic has demonstrated these optimal anti-nauseant and anti-emetic effects for the treatment of NVP.

 

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Acknowledgement:

GK was a paid consultant for Duchesnay Inc.