Diclectin 10/10mg

Interactions with herbal products have not been established.

Interactions with food have not been established.

Interactions with laboratory tests have not been established.

No formal drug-drug interaction studies have been performed with Diclectin.

Two Diclectin delayed release tablets at bedtime to control nausea and vomiting occurring in the morning; additionally one delayed release tablet in the morning and one delayed release tablet mid-afternoon to control symptoms throughout the day. The dosage schedule may be individualized according to timing, duration, severity and frequency of the symptoms experienced by the patient. Diclectin can be prescribed in any trimester of pregnancy.

Diclectin is a delayed-release formulation that works optimally when given 4 to 6 hours prior to anticipated onset of symptoms. The delay in action may be prolonged when tablets are taken with food.

Diclectin tablets being of a delayed release formulation should not be prescribed on an as needed basis (prn). It is important that Diclectin is taken daily for optimal effect.

A gradual tapering dose of Diclectin is recommended at the time of discontinuation to prevent a sudden onset of symptoms.

Diclectin is to be taken orally. Diclectin tablets are a delayed release formulation therefore they should not be crushed or split.

In the event that a dose is missed, it should be taken as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped. The prescribed dosing schedule should be continued.

The most common adverse reaction associated with doxylamine succinate is drowsiness. Other adverse drug reactions associated with doxylamine succinate may include: vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention or insomnia.

Pyridoxine is a vitamin that is generally recognized as having no adverse effects.

None reported.

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.

In a randomized, double-blind, multi-center study in 2308 women with nausea and vomiting of pregnancy, various combinations of doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride (each at 10 mg) were compared with placebo in an 8-way study design. The incidence of adverse reactions was 8.7% in the doxylamine/pyridoxine group versus 11.2% in the placebo group. In the doxylamine/pyridoxine group the most common adverse reactions were drowsiness (15/265, 5.7%), dizziness (3/265, 1.1%), fatigue or lethargy (2/265, 0.75%), gastric irritation, heartburn or indigestion (2/265, 0.75%) and headache (2/265, 0.75%). Corresponding values for the placebo group were drowsiness 8/269 (3%), dizziness 2/269 (0.75%), fatigue or lethargy 3/269 (1.1%), gastric irritation, heartburn or indigestion 0/269 (0%) and headache 4/269 (1.5%).

In a double-blind comparison study of placebo and combination drug product (doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride) in 81 patients 18 adverse events were reported (22.2%). In the active group 12 side effects were reported (29.2%) versus 6 (15%) in the placebo group. Feelings of weakness were reported by 2/41 (5%) in the active group versus 0% in the placebo group, tiredness by 2/41 (5%) in the active versus 2/40 (5%) in the placebo group and drowsiness by 3/41 (7%) in the active versus 1/40 (2.5%) in the placebo group. Also reported were: lack of energy, constipation, furry sensation in mouth, wind and headache.

Atanackovic et al., 2001 evaluated the safety of higher than standard doses of Diclectin in 225 pregnant women with nausea and vomiting of pregnancy in an observational, prospective study. A total of 123 women received standard doses of up to 4 tablets a day and 102 women received a higher than standard dose (“supradose”) of 5 to 12 tablets/day. Despite a twice larger mean maximal dose of Diclectin, women receiving the supradose did not report more prevalent adverse effects of Diclectin. In the supradose group, 32% (31/97) reported sleepiness, tiredness and/or drowsiness compared with 35% (42/122) among the standard dose recipients. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1-12 tablets).

Since 1996, the Motherisk{*Motherisk: Hospital for Sick Children, 555 University Ave., Toronto, ON (M5G 1X8). www.motherisk.org. 1-800-436-8477.} Program at the Hospital for Sick Children has maintained a toll-free bilingual (French-English) Nausea and Vomiting of Pregnancy (NVP) Helpline (1-800-436-8477) with the ongoing support of Duchesnay Inc. This service is available to women and healthcare professionals that would like to discuss the impact and management of NVP. Early recognition and treatment can prevent the progression of NVP to hyperemesis gravidarum and maternal and fetal complications.

Further to being a disease management line the NVP Helpline is acting as a surveillance program for Diclectin. This service provides continuous monitoring of adverse events and the safe use of Diclectin during pregnancy while generating valuable research data.

Diclectin may have a minor to moderate influence on the ability to drive and use machines. Because of potential drowsiness, Diclectin should be prescribed with caution for patients who must drive automobiles or operate machinery.

There is no information to indicate that abuse or dependency occurs with the concentration of doxylamine succinate and pyridoxine hydrochloride found in Diclectin.

A case-control investigation was performed by the Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) to analyze the incidence of childhood cancer in relation to the maternal consumption of doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride. Dicyclomine hydrochloride was a component of the earlier formulations intended for nausea and vomiting of pregnancy that has since been removed due to a lack of evidence of contribution to efficacy.

Data were derived from interview reports and medical records of 555 mothers of children (under 15 years of age) with cancer and 1110 mothers of matched control children. Maternal ingestion of the antiemetic drug during the index pregnancy was not associated with increasing the risk of childhood malignant disease. No dose-response relationship was evident.

Due to the anticholinergic properties of antihistamines, caution should be used when Diclectin is taken concurrently with other medications or alcohol.

Diclectin is intended for use in pregnant women. There has been a vast clinical experience (>30 million pregnancies worldwide) regarding the use of a combination of doxylamine succinate, pyridoxine hydrochloride with or without dicyclomine hydrochloride in this population.

Diclectin has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. Two separate meta-analyses have been conducted that have assessed pregnancy outcome following the use of a combination of doxylamine succinate, pyridoxine hydrochloride with or without dicyclomine hydrochloride during the first trimester. McKeigue et al. conducted a meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991. No increased risk for malformations was found in first trimester exposures to doxylamine succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta-analysis, conducted by Einarson et al. incorporated 12 cohort and 5 case-control studies. No statistically significant relationships were found between first trimester use of the combination doxylamine succinate, pyridoxine hydrochloride with or without dicyclomine hydrochloride and fetal abnormalities.

In 1989, a report on the safety of Diclectin for use in the management of nausea and vomiting of pregnancy was prepared by a panel of experts for the Special Advisory Committee on Reproductive Physiology to the Health Protection Branch of Health Canada. The Motherisk Program at the Hospital for Sick Children systematically reviewed the literature to develop an evidence-based algorithm on the safety and efficacy of treatments for nausea and vomiting of pregnancy. Doxylamine succinate combined with pyridoxine hydrochloride (Diclectin) is listed as first line therapy on this algorithm. Similarly, the 2002 Society of Obstetricians and Gynaecologists of Canada (SOGC) Clinical Practice Guidelines on the management of nausea and vomiting of pregnancy recommend that this formulation be the standard of care, since it has the greatest evidence to support its safety and efficacy.

Atanackovic et al. evaluated the safety of higher than standard doses of Diclectin in 225 pregnant women with Nausea and Vomiting of Pregnancy (NVP) in an observational, prospective study. A total of 123 women received standard doses of up to 4 tablets a day and 102 women received a higher than standard dose (“supradose”) of 5 to 12 tablets/day. Despite a twice larger mean maximal dose of Diclectin, women receiving the supradose did not report more prevalent adverse effects while taking Diclectin. The lack of any major malformation with the supradose strongly suggests that the higher dose is not teratogenic. It was concluded that supradoses of 5 to 12 tablets daily did not appear to affect the incidence of maternal adverse effects or pregnancy outcome.

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. Published data clearly shows that Diclectin use in pregnancy does not increase a woman's baseline risk of having a child with a major malformation. Diclectin has the highest safety rating in Briggs: “Category A”. No other prescription drug has been more extensively studied for safety in pregnancy.

There are no published reports describing the use of Diclectin during lactation. However, the passage of doxylamine succinate into breast milk can be expected. Effects on a nursing infant, if any, are unknown, but sedative and other antihistamine actions are a potential concern. Pyridoxine hydrochloride is excreted into breast milk, but in the doses provided in Diclectin, presents no risk to a nursing infant.

No data is available on differences in the pharmacokinetics of doxylamine succinate or pyridoxine hydrochloride in patients with hepatic insufficiency.

Diclectin: A randomized open-label, 2-way crossover relative bioavailability study in 22 healthy adult females compared the pharmacokinetics after a single dose of two (2×[10 mg+10 mg]) Diclectin tablets under fed and fasted conditions. The administration of food delayed the absorption of both doxylamine and pyridoxine by approximately 5 hours. However, this delay did not affect the peak concentration or extent of absorption of doxylamine, as both the C_max and AUC were not distinguishable between treatments. In contrast, the peak concentration and extent of absorption of pyridoxine were considerably reduced when administered with food. The effect of food on the pyridoxine component is more complex, in that pyridoxine, pyridoxal and pyridoxal 5'-phosphate, also contribute to the biological activity. Although pyridoxal peak concentrations are somewhat reduced, pyridoxal 5'-phosphate peak concentrations are slightly increased and AUC values for both pyridoxal and pyridoxal 5'-phosphate are not affected by administration under fed conditions. Total pyridoxine mean peak concentrations are slightly reduced but extent of absorption, as measured by AUC, is unaffected by treatment.

Pyridoxine Hydrochloride: Pyridoxine is readily absorbed in the gastrointestinal tract, mainly in the jejunum. Pyridoxine is primarily metabolized in the liver; following phosphorylation, its main active metabolite, pyridoxal 5'-phosphate, is released into the circulation (accounting for at least 60% of circulating vitamin B6) and is highly protein bound; primarily to albumin. The metabolic scheme for pyridoxine is complex, with formation of primary and secondary metabolites along with interconversion back to pyridoxine. These metabolites including pyridoxal, have biologic activity. The major metabolite 4-pyridoxic acid, is inactive and is excreted in urine.

Doxylamine Succinate: Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl and N, N-didesmethyldoxylamine, which are excreted by the kidney.

Doxylamine can cross the blood-brain barrier and has a high affinity for H1 receptors in the brain.

Diclectin (doxylamine succinate and pyridoxine hydrochloride) provides the action of two unrelated compounds. Doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6) provide anti-nauseant and anti-emetic activity. The delayed action of Diclectin permits the nighttime dose to be effective in the morning hours, when the patient needs it most.

No data is available on differences in the pharmacokinetics of either doxylamine succinate or pyridoxine hydrochloride in different races.

No data is available on differences in the pharmacokinetics of doxylamine succinate in renal insufficiency. For pyridoxine hydrochloride some metabolites are excreted renally. There are no data to suggest that this should alter the current dosage recommendation of Diclectin.

No data is available.