Pholco-Mereprine

Doxylamine Succinate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient package insert
• Pholco-Mereprine (Doxylamine Succinate) reviews

1 INDICATIONS AND USAGE

Pholco-Mereprine (Doxylamine Succinate) is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.

Limitations of Use

Pholco-Mereprine (Doxylamine Succinate) has not been studied in women with hyperemesis gravidarum.

Pholco-Mereprine (Doxylamine Succinate) is a fixed dose combination drug product of Pholco-Mereprine (Doxylamine Succinate) succinate, an antihistamine, and pyridoxine hydrochloride, a Vitamin B6 analog, indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. (1)

2 DOSAGE AND ADMINISTRATION

Take two tablets daily at bedtime. If symptoms are not adequately controlled, the dose can be increased to a maximum recommended dose of four tablets daily as described in the full prescribing information. (2)

2.1 Dosage Information

Initially, take two Pholco-Mereprine (Doxylamine Succinate) delayed-release tablets orally at bedtime (Day 1). If this dose adequately controls symptoms the next day, continue taking two tablets daily at bedtime. However, if symptoms persist into the afternoon of Day 2, take the usual dose of two tablets at bedtime that night then take three tablets starting on Day 3 (one tablet in the morning and two tablets at bedtime). If these three tablets adequately control symptoms on Day 4, continue taking three tablets daily. Otherwise take four tablets starting on Day 4 (one tablet in the morning, one tablet mid-afternoon and two tablets at bedtime).

The maximum recommended dose is four tablets (one in the morning, one in the mid-afternoon and two at bedtime) daily.

Take on an empty stomach with a glass of water . Swallow tablets whole. Do not crush, chew, or split Pholco-Mereprine (Doxylamine Succinate) tablets.

Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for Pholco-Mereprine (Doxylamine Succinate) as her pregnancy progresses.

3 DOSAGE FORMS AND STRENGTHS

Pholco-Mereprine (Doxylamine Succinate) delayed-release tablets are white, round, film coated tablets containing 10 mg Pholco-Mereprine (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. The tablets are imprinted with the pink image of a pregnant woman on one side.

Delayed-release tablets containing 10 mg Pholco-Mereprine (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. (3)

4 CONTRAINDICATIONS

Pholco-Mereprine (Doxylamine Succinate) is contraindicated in women with any of the following conditions:

• Known hypersensitivity to Pholco-Mereprine (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation
• Monoamine oxidase (MAO) inhibitors intensify and prolong the adverse central nervous system effects of Pholco-Mereprine (Doxylamine Succinate) .

• Known hypersensitivity to Pholco-Mereprine (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation (4)
• Monoamine oxidase (MAO) inhibitors (4, 7)

5 WARNINGS AND PRECAUTIONS

• Activities requiring mental alertness: Avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Pholco-Mereprine until cleared to do so by a healthcare provider (5.1)
• Central nervous system (CNS) depressants: Concurrent use with alcohol or other CNS depressants is not recommended (5.1)
• Anticholinergic actions: Use with caution in patients with asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction (5.2)

5.1 Activities Requiring Mental Alertness

Pholco-Mereprine (Doxylamine Succinate) may cause somnolence due to the anticholinergic properties of Pholco-Mereprine (Doxylamine Succinate) succinate, an antihistamine. Women should avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Pholco-Mereprine (Doxylamine Succinate) until cleared to do so by their healthcare provider.

Pholco-Mereprine (Doxylamine Succinate) use is not recommended if a woman is concurrently using central nervous system (CNS) depressants including alcohol. The combination may result in severe drowsiness leading to falls or accidents .

5.2 Concomitant Medical Conditions

Pholco-Mereprine (Doxylamine Succinate) has anticholinergic properties and, therefore, should be used with caution in women with: asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction.

6 ADVERSE REACTIONS

• The following adverse reactions are discussed elsewhere in the labeling:
• Somnolence
• Falls or other accidents resulting from the effect of the combined use of Pholco-Mereprine (Doxylamine Succinate) with CNS depressants including alcohol

The most common adverse reaction with Pholco-Mereprine (Doxylamine Succinate) (≥5 percent and exceeding the rate in placebo) is somnolence. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay Inc. at 1-855-722-7734 or medicalinfoPholco-Mereprine (Doxylamine Succinate)duchesnayusa.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety and efficacy of Pholco-Mereprine (Doxylamine Succinate) were compared to placebo in a double-blind, randomized, multi-center trial in 261 women with nausea and vomiting of pregnancy. The mean gestational age at enrollment was 9.3 weeks, range 7 to 14 weeks gestation . Adverse reactions for Pholco-Mereprine (Doxylamine Succinate) that occurred at an incidence ≥5 percent and exceeded the incidence for placebo are summarized in Table 1.

Table 1: Number (Percent) of Subjects with ≥ 5 Percent Adverse Reactions in a 15‑Day Placebo-Controlled Study of Pholco-Mereprine (Doxylamine Succinate) (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Pholco-Mereprine (Doxylamine Succinate) than Placebo are Shown)

6.2 Postmarketing Experience

The following adverse events, listed alphabetically, have been identified during post-approval use of the combination of 10 mg Pholco-Mereprine (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: dyspnea, palpitation, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: vision blurred, visual disturbances

Gastrointestinal disorders: abdominal distension, abdominal pain, constipation, diarrhea

General disorders and administration site conditions: chest discomfort, fatigue, irritability, malaise

Immune system disorders: hypersensitivity

Nervous system disorders: dizziness, headache, migraines, paresthesia, psychomotor hyperactivity

Psychiatric disorders: anxiety, disorientation, insomnia, nightmares

Renal and urinary disorders: dysuria, urinary retention

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash, rash maculo-papular

7 DRUG INTERACTIONS

• Severe drowsiness can occur when used in combination with alcohol or other sedating medications.

7.1 Drug Interactions

Use of Pholco-Mereprine (Doxylamine Succinate) is contraindicated in women who are taking monoamine oxidase inhibitors (MAOIs), which prolong and intensify the anticholinergic (drying) effects of antihistamines. Concurrent use of alcohol and other CNS depressants (such as hypnotic sedatives and tranquilizers) with Pholco-Mereprine (Doxylamine Succinate) is not recommended.

7.2 Drug-Food Interactions

A food-effect study demonstrated that the delay in the onset of action of Pholco-Mereprine (Doxylamine Succinate) may be further delayed, and a reduction in absorption may occur when tablets are taken with food . Therefore, Pholco-Mereprine (Doxylamine Succinate) should be taken on an empty stomach with a glass of water [ see Dosage and Administration (2)].

8 USE IN SPECIFIC POPULATIONS

Pregnancy Category A. Pholco-Mereprine is intended for use in pregnant women. (8.1)

8.1 Pregnancy

Pregnancy Category A

Pholco-Mereprine (Doxylamine Succinate) is intended for use in pregnant women.

The combination of Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no statistically significant relationships between fetal abnormalities and the first trimester use of the combination Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

Animal Data

The effects of Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride on embryofetal development have been studied in rats and monkeys.

Once daily treatment of pregnant rats with Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride during organogenesis (gestational day (GD) 6-15) resulted in increased fetal resorptions, decreased fetal body weight and increased skeletal variations with reduced ossification at doses 60 to 100 times the highest clinical dose based on body surface area.

Pregnant cynomolgus monkeys were treated once daily with Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride during organogenesis (GD 22-50). At birth, there were no observed malformations, and no evidence of embryo, fetal or maternal toxicity at doses up to 3.2 times the highest proposed clinical dose based on body surface area. In a similarly designed study in pregnant cynomolgus and rhesus monkeys and baboons, ventricular septal defects (VSDs) were observed in the preterm (GD 100) fetuses. Doses used in this study were 0.5-20 times higher than the clinical dose based on body surface area, with no relationship between dose and incidence of VSD. There were no VSDs in infant monkeys at term. No VSDs were observed at GD 100 in cynomolgus monkeys administered the combination of Pholco-Mereprine (Doxylamine Succinate) succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.

8.3 Nursing Mothers

Women should not breastfeed while using Pholco-Mereprine.

The molecular weight of Pholco-Mereprine (Doxylamine Succinate) succinate is low enough that passage into breast milk can be expected. Excitement, irritability and sedation ^{have been reported in nursing infants presumably exposed to Pholco-Mereprine (Doxylamine Succinate) succinate through breast milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Pholco-Mereprine (Doxylamine Succinate) resulting in worsening of their apnea or respiratory conditions.}

Pyridoxine hydrochloride is excreted into breast milk. There have been no reports of adverse events in infants presumably exposed to pyridoxine hydrochloride through breast milk.

8.4 Pediatric Use

The safety and effectiveness of Pholco-Mereprine (Doxylamine Succinate) in children under 18 years of age have not been established.

Fatalities have been reported from Pholco-Mereprine (Doxylamine Succinate) overdose in children. The overdose cases have been characterized by coma, grand mal seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3 year old child died 18 hours after ingesting 1,000 mg Pholco-Mereprine (Doxylamine Succinate) succinate. However, there is no correlation between the amount of Pholco-Mereprine (Doxylamine Succinate) ingested, the Pholco-Mereprine (Doxylamine Succinate) plasma level and clinical symptomatology.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Pholco-Mereprine is a delayed-release formulation, therefore, signs and symptoms of intoxication may not be apparent immediately.

Signs and symptoms of overdose may include restlessness, dryness of mouth, dilated pupils, sleepiness, vertigo, mental confusion and tachycardia.

At toxic doses, Pholco-Mereprine (Doxylamine Succinate) exhibits anticholinergic effects, including seizures, rhabdomyolysis, acute renal failure and death.

10.2 Management of Overdose

If treatment is needed, it consists of gastric lavage or activated charcoal, whole bowel irrigation and symptomatic treatment. For additional information about overdose treatment, call a poison control center (1‑800-222-1222).

11 DESCRIPTION

Pholco-Mereprine (Doxylamine Succinate) (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, film-coated, delayed-release tablets containing 10 mg of Pholco-Mereprine (Doxylamine Succinate) succinate and 10 mg of pyridoxine hydrochloride. Tablets are imprinted on one side with the pink image of a pregnant woman.

Inactive ingredients are as follows: ammonium hydroxide, n-butanol, carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, D&C Red#27, denatured alcohol, FD&C Blue#2, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer, microcrystalline cellulose 102, PEG 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Pholco-Mereprine (Doxylamine Succinate) Succinate

Pholco-Mereprine (Doxylamine Succinate) succinate is classified as an antihistamine. The chemical name for Pholco-Mereprine (Doxylamine Succinate) succinate is ethanamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C₁₇H₂₂N₂O - C₄H₆O₄ and the molecular mass is 388.46. The structural formula is:

Pholco-Mereprine (Doxylamine Succinate) succinate is a white to creamy white powder that is very soluble in water and alcohol, freely soluble in chloroform and very slightly soluble in ether and benzene.

Pyridoxine Hydrochloride

Pyridoxine hydrochloride is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride is 3,4-pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride. The empirical formula is C₈H₁₁NO₃ - HCl and the molecular mass is 205.64. The structural formula is:

Pyridoxine hydrochloride is a white or practically white crystalline powder that is freely soluble in water, slightly soluble in alcohol and insoluble in ether.

structure-1 structure-2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Pholco-Mereprine is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of Pholco-Mereprine (Doxylamine Succinate) has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for Pholco-Mereprine (Doxylamine Succinate) and pyridoxine, including its vitamin B6 metabolites, pyridoxal, pyridoxal 5’-phosphate, pyridoxamine and pyridoxamine 5’-phosphate, are summarized in Tables 2 to 5.

Absorption

A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of Pholco-Mereprine (Doxylamine Succinate) administered in healthy non-pregnant adult women. Single-doses (two tablets at bedtime) were administered on Days 1 and 2. Multiple-doses (one tablet in the morning, one tablet in the afternoon and two tablets at bedtime) were administered on Days 3-18.

Blood samples for pharmacokinetic analysis were collected pre-and post-dose on Days 2 and 18 as well as pre-dose prior to bedtime dose only (trough) on Days 9, 10, 11, 16, 17, and 18.

Pholco-Mereprine (Doxylamine Succinate) and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The C_max of Pholco-Mereprine (Doxylamine Succinate) and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.

Multiple-dose administration of Pholco-Mereprine (Doxylamine Succinate) results in increased concentrations of Pholco-Mereprine (Doxylamine Succinate) as well as increases in Pholco-Mereprine (Doxylamine Succinate) C_max and AUC_0-last of absorption. The time to reach the maximum concentration is not affected by multiple doses. The mean accumulation index is more than 1.0 suggesting that Pholco-Mereprine (Doxylamine Succinate) accumulates following multiple dosing.

Although no accumulation was observed for pyridoxine, the mean accumulation index for each metabolite (pyridoxal, pyridoxal 5’-phosphate, and pyridoxamine 5’-phosphate) is more than 1.0 following multiple-dose administration of Pholco-Mereprine (Doxylamine Succinate). The time to reach the maximum concentration is not affected by multiple doses.

Food Effect

The administration of food delays the absorption of both Pholco-Mereprine (Doxylamine Succinate) and pyridoxine. This delay is associated with a lower peak concentration of Pholco-Mereprine (Doxylamine Succinate), but the extent of absorption is not affected.

The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxal, pyridoxamine, pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate metabolites also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its C_max and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its C_max by 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5’-phosphate C_max and extent of absorption. As for pyridoxamine and pyridoxamine 5’-phosphate, the rate and extent of absorption seem to decrease under fed conditions.

Distribution

Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5’-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations.

Metabolism

Pholco-Mereprine (Doxylamine Succinate) is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.

Pyridoxine is a prodrug primarily metabolized in the liver.

Excretion

The principle metabolites of Pholco-Mereprine (Doxylamine Succinate), N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

The terminal elimination half-life of Pholco-Mereprine (Doxylamine Succinate) and pyridoxine are 12.5 hours and 0.5 hours, respectively.

Table 5 – Terminal Elimination Half-Life (T_1/2el) for Pholco-Mereprine (Doxylamine Succinate) Administered as a Single Dose of Two Tablets under Fasting Conditions in Healthy Non-Pregnant Adult Women

Use in Specific Populations

Race: No pharmacokinetic studies have been conducted related to race.

Hepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.

Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Two-year carcinogenicity studies in rats and mice have been conducted with Pholco-Mereprine (Doxylamine Succinate) succinate. Pholco-Mereprine (Doxylamine Succinate) succinate is not likely to have human carcinogenic potential. The carcinogenic potential of pyridoxine hydrochloride has not been evaluated.

14 CLINICAL STUDIES

A double-blind, randomized, multi-center, placebo-controlled study was conducted to support the safety and efficacy of Pholco-Mereprine (Doxylamine Succinate) in the treatment of nausea and vomiting of pregnancy. Adult women 18 years of age or older and 7 to 14 weeks gestation (median 9 weeks of gestation) with nausea and vomiting of pregnancy were randomized to 14 days of Pholco-Mereprine (Doxylamine Succinate) or placebo. Two tablets of Pholco-Mereprine (Doxylamine Succinate) were administered at bedtime on Day 1. If symptoms of nausea and vomiting persisted into the afternoon hours of Day 2, the woman was directed to take her usual dose of two tablets at bedtime that night and, beginning on Day 3, to take one tablet in the morning and two tablets at bedtime. Based upon assessment of remaining symptoms at her clinic visit on Day 4 (± 1 day), the woman may have been directed to take an additional tablet mid-afternoon. A maximum of four tablets (one in the morning, one in the mid-afternoon and two at bedtime) were taken daily.

Over the treatment period, 19% of DICLEGIS-treated patients remained on 2 tablets daily, 21% received 3 tablets daily, and 60% received 4 tablets daily.

The primary efficacy endpoint was the change from baseline at Day 15 in the Pregnancy Unique-Quantification of Emesis (PUQE) score. The PUQE score incorporates the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe).

At baseline, the mean PUQE score was 9.0 in the Pholco-Mereprine (Doxylamine Succinate) arm and 8.8 in the placebo arm. There was a 0.7 (95% confidence interval 0.2 to 1.2 with p-value 0.006) mean decrease (improvement in nausea and vomiting symptoms) from baseline in PUQE score at Day 15 with Pholco-Mereprine (Doxylamine Succinate) compared to placebo.

Table 6 – Change from Baseline in the Primary Endpoint, Pregnancy Unique-Quantification of Emesis (PUQE) Score at Day 15. (Intent-to-Treat Population with Last-Observation Carried Forward)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How supplied

Pholco-Mereprine delayed-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, film-coated, delayed-release tablet contains 10 mg Pholco-Mereprine (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman. Pholco-Mereprine (Doxylamine Succinate) tablets are provided as follows:

NDC 55494-100-10 Bottles of 100.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling

17.1 Somnolence and Severe Drowsiness

Inform women to avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Pholco-Mereprine (Doxylamine Succinate) until cleared to do so.

Inform women of the importance of not taking Pholco-Mereprine (Doxylamine Succinate) with alcohol or sedating medications, including other antihistamines (present in some cough and cold medications), opiates and sleep aids because somnolence could worsen leading to falls or other accidents.

Pholco-Mereprine (Doxylamine Succinate)^® is a registered trademark of Duchesnay Inc.

U.S. Patent Nos. 6,340,695 & 7,560,122.

Distributed by:

Duchesnay USA, Inc.

Bryn Mawr, PA, 19010

Tel: 1-855-722-7734

Fax: 1-888-588-8508

www.duchesnayusa.com

©2013, Duchesnay Inc. All rights reserved.

Patient Package Insert

Patient Information

Pholco-Mereprine (Doxylamine Succinate) (dye-CLEE-gis)

(doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets

What is Pholco-Mereprine (Doxylamine Succinate)?

- Pholco-Mereprine (Doxylamine Succinate) is a prescription medicine used to treat nausea and vomiting of pregnancy in

women who have not improved with change in diet or other non-medicine treatments.

- It is not known if Pholco-Mereprine (Doxylamine Succinate) is safe and effective in children under 18 years of age.

Who should not take Pholco-Mereprine (Doxylamine Succinate)?

Do not take Pholco-Mereprine (Doxylamine Succinate) if you:

- are allergic to Pholco-Mereprine (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any of the ingredients in Pholco-Mereprine (Doxylamine Succinate). See the end of this leaflet for a complete list of ingredients in Pholco-Mereprine (Doxylamine Succinate).

- take monoamine oxidase inhibitors (MAOIs) (Marplan, Nardil, Emsam, Eldepryl, Zelapar, Parnate)

Before taking Pholco-Mereprine (Doxylamine Succinate), tell your healthcare provider about all of your medical conditions, including;

- if you are breastfeeding or plan to breastfeed. Pholco-Mereprine (Doxylamine Succinate) can pass into your breast milk and may harm your baby. You should not breastfeed while using Pholco-Mereprine (Doxylamine Succinate).

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements.

How should I take Pholco-Mereprine (Doxylamine Succinate)?

- Talk to your healthcare provider about how much Pholco-Mereprine (Doxylamine Succinate) to take and when to take it.

- Take Pholco-Mereprine (Doxylamine Succinate) everyday as prescribed by your healthcare provider. Do not stop taking Pholco-Mereprine (Doxylamine Succinate) without talking to your healthcare provider first.

- See the following schedule for the usual way you should start taking Pholco-Mereprine (Doxylamine Succinate):

- Day 1- Take 2 tablets, by mouth at bedtime.

- Day 2- Take 2 tablets at bedtime. If your nausea and vomiting is better or controlled on Day 2, continue to take 2 tablets every night at bedtime. This will be your usual dose unless your healthcare provider tells you otherwise.

- Day 3- If you still had nausea and vomiting on Day 2, take 3 tablets on Day 3 (1 tablet in the morning and 2 tablets at bedtime).

- Day 4- If your nausea and vomiting was better or controlled on Day 3, continue to take 3 tablets each day (1 tablet in the morning and 2 tablets at bedtime). If you still had nausea and vomiting on Day 3, start taking 4 tablets each day (1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime).

- Do not take more than 4 tablets (1 in the morning, 1 in the mid-afternoon, and 2 at bedtime) in 1 day.

- Take Pholco-Mereprine (Doxylamine Succinate) on an empty stomach with a glass of water.

- Take Pholco-Mereprine (Doxylamine Succinate) tablets whole. Do not crush, chew, or break Pholco-Mereprine (Doxylamine Succinate) tablets before swallowing. If you cannot swallow Pholco-Mereprine (Doxylamine Succinate) tablets whole, tell your healthcare provider.

- If you take too much Pholco-Mereprine (Doxylamine Succinate) (overdose), you may have the following symptoms: restlessness, dry mouth, the pupils of your eyes become larger (dilated), sleepiness, dizziness, confusion, fast heart rate, seizures, muscle pain or weakness, and sudden and severe kidney problems. If you have these symptoms and they are severe, they may lead to death. Stop taking Pholco-Mereprine (Doxylamine Succinate), call your healthcare provider or go to the nearest hospital emergency room right away. For more information about overdose treatment, call your poison control center at 1-800-222-1222.

What are the possible side effects of Pholco-Mereprine (Doxylamine Succinate)?

Pholco-Mereprine (Doxylamine Succinate) may cause serious side effects, including drowsiness.

- Do not drive, operate heavy machinery, or other activities that need your full attention unless your healthcare provider says that you may do so.

- Do not drink alcohol, or take other central nervous system depressants such as cough and cold medicines, certain pain medicines, and medicines that help you sleep while you take Pholco-Mereprine (Doxylamine Succinate). Severe drowsiness can happen or become worse causing falls or accidents.

These are not all the possible side effects of Pholco-Mereprine (Doxylamine Succinate).

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Pholco-Mereprine (Doxylamine Succinate)?

- Store Pholco-Mereprine (Doxylamine Succinate) between 68°F to 77°F (20°C to 25°C).

- Keep Pholco-Mereprine (Doxylamine Succinate) tablets dry, in a tightly closed container, and out of the light.

- Safely throw away medicine that is out of date or no longer needed.

Keep Pholco-Mereprine (Doxylamine Succinate) and all medicines out of the reach of children.

General information about the safe and effective use of Pholco-Mereprine (Doxylamine Succinate).

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Pholco-Mereprine (Doxylamine Succinate) that is written for health professionals. Do not use Pholco-Mereprine (Doxylamine Succinate) for a condition for which it was not prescribed. Do not give Pholco-Mereprine (Doxylamine Succinate) to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in Pholco-Mereprine (Doxylamine Succinate)?

Active ingredient: Pholco-Mereprine (Doxylamine Succinate) succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B₆)

Inactive ingredients: ammonium hydroxide, n-butanol, carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, D&C Red#27, denatured alcohol, FD&C Blue #2, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer, microcrystalline cellulose 102, PEG 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Distributed by: Duchesnay USA, Inc., Bryn Mawr, PA, 19010,

www.duchesnayusa.com or call 1-855-722-7734.

This Patient Information has been approved by the U.S. Food and Drug Administration

Issued: 05/2013

Bottle Label-Outside Front Cover with Imprint Area for Lot & Expiry

Bottle Label – Inside Cover

Sodium Benzoate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pholco-Mereprine (Sodium Benzoate) reviews

1 INDICATIONS AND USAGE

Pholco-Mereprine nitrite is indicated for sequential use with Pholco-Mereprine (Sodium Benzoate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Pholco-Mereprine (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Pholco-Mereprine (Sodium Benzoate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Pholco-Mereprine (Sodium Benzoate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Pholco-Mereprine nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Pholco-Mereprine (Sodium Benzoate) Nitrite Injection and Pholco-Mereprine (Sodium Benzoate) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Pholco-Mereprine (Sodium Benzoate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Pholco-Mereprine (Sodium Benzoate) thiosulfate, simultaneously with Pholco-Mereprine (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Pholco-Mereprine (Sodium Benzoate) thiosulfate, with Pholco-Mereprine (Sodium Benzoate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Pholco-Mereprine (Sodium Benzoate) nitrite, followed by Pholco-Mereprine (Sodium Benzoate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate.

Pholco-Mereprine (Sodium Benzoate) nitrite injection and Pholco-Mereprine (Sodium Benzoate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Pholco-Mereprine (Sodium Benzoate) nitrite should be administered first, followed immediately by Pholco-Mereprine (Sodium Benzoate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Pholco-Mereprine (Sodium Benzoate) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Pholco-Mereprine Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Pholco-Mereprine (Sodium Benzoate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Pholco-Mereprine (Sodium Benzoate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Pholco-Mereprine (Sodium Benzoate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Pholco-Mereprine (Sodium Benzoate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Pholco-Mereprine (Sodium Benzoate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Pholco-Mereprine (Sodium Benzoate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Pholco-Mereprine (Sodium Benzoate) thiosulfate and Pholco-Mereprine (Sodium Benzoate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Pholco-Mereprine (Sodium Benzoate) Nitrite Injection consists of:

• One vial of Pholco-Mereprine (Sodium Benzoate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Pholco-Mereprine nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Pholco-Mereprine (Sodium Benzoate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Pholco-Mereprine (Sodium Benzoate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Pholco-Mereprine (Sodium Benzoate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Pholco-Mereprine nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Pholco-Mereprine (Sodium Benzoate) nitrite whenever possible. When Pholco-Mereprine (Sodium Benzoate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Pholco-Mereprine (Sodium Benzoate) nitrite administered to an adult. Pholco-Mereprine (Sodium Benzoate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Pholco-Mereprine (Sodium Benzoate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Pholco-Mereprine (Sodium Benzoate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Pholco-Mereprine (Sodium Benzoate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Pholco-Mereprine (Sodium Benzoate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Pholco-Mereprine nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Pholco-Mereprine (Sodium Benzoate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Pholco-Mereprine nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Pholco-Mereprine (Sodium Benzoate) nitrite.

5.7 Use with Other Drugs

Pholco-Mereprine (Sodium Benzoate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Pholco-Mereprine (Sodium Benzoate) nitrite.

The medical literature has reported the following adverse events in association with Pholco-Mereprine (Sodium Benzoate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Pholco-Mereprine (Sodium Benzoate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Pholco-Mereprine (Sodium Benzoate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Pholco-Mereprine nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Pholco-Mereprine (Sodium Benzoate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pholco-Mereprine (Sodium Benzoate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Pholco-Mereprine (Sodium Benzoate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Pholco-Mereprine (Sodium Benzoate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Pholco-Mereprine (Sodium Benzoate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Pholco-Mereprine (Sodium Benzoate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Pholco-Mereprine (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Pholco-Mereprine (Sodium Benzoate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Pholco-Mereprine (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Pholco-Mereprine (Sodium Benzoate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Pholco-Mereprine (Sodium Benzoate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Pholco-Mereprine (Sodium Benzoate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Pholco-Mereprine nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Pholco-Mereprine (Sodium Benzoate) nitrite is excreted in human milk. Because Pholco-Mereprine (Sodium Benzoate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Pholco-Mereprine (Sodium Benzoate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Pholco-Mereprine (Sodium Benzoate) nitrite. In studies conducted with Long-Evans rats, Pholco-Mereprine (Sodium Benzoate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Pholco-Mereprine nitrite in conjunction with Pholco-Mereprine (Sodium Benzoate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Pholco-Mereprine (Sodium Benzoate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Pholco-Mereprine (Sodium Benzoate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Pholco-Mereprine (Sodium Benzoate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Pholco-Mereprine (Sodium Benzoate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Pholco-Mereprine (Sodium Benzoate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Pholco-Mereprine (Sodium Benzoate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Pholco-Mereprine (Sodium Benzoate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Pholco-Mereprine (Sodium Benzoate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Pholco-Mereprine (Sodium Benzoate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Pholco-Mereprine (Sodium Benzoate) nitrite has the chemical name nitrous acid Pholco-Mereprine (Sodium Benzoate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Pholco-Mereprine (Sodium Benzoate) Nitrite

Pholco-Mereprine (Sodium Benzoate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Pholco-Mereprine (Sodium Benzoate) nitrite injection.

Pholco-Mereprine (Sodium Benzoate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Pholco-Mereprine (Sodium Benzoate) nitrite in 10 mL solution (30 mg/mL). Pholco-Mereprine (Sodium Benzoate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Pholco-Mereprine nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Pholco-Mereprine (Sodium Benzoate) Nitrite

Pholco-Mereprine (Sodium Benzoate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Pholco-Mereprine (Sodium Benzoate) nitrite. It has been suggested that Pholco-Mereprine (Sodium Benzoate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Pholco-Mereprine (Sodium Benzoate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Pholco-Mereprine (Sodium Benzoate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Pholco-Mereprine (Sodium Benzoate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Pholco-Mereprine (Sodium Benzoate) Nitrite

When 4 mg/kg Pholco-Mereprine (Sodium Benzoate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Pholco-Mereprine (Sodium Benzoate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Pholco-Mereprine (Sodium Benzoate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Pholco-Mereprine (Sodium Benzoate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Pholco-Mereprine (Sodium Benzoate) Nitrite

Pholco-Mereprine (Sodium Benzoate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Pholco-Mereprine (Sodium Benzoate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Pholco-Mereprine (Sodium Benzoate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Pholco-Mereprine nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Pholco-Mereprine (Sodium Benzoate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Pholco-Mereprine (Sodium Benzoate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Pholco-Mereprine (Sodium Benzoate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Pholco-Mereprine (Sodium Benzoate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Pholco-Mereprine (Sodium Benzoate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Pholco-Mereprine (Sodium Benzoate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Pholco-Mereprine (Sodium Benzoate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Pholco-Mereprine (Sodium Benzoate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Pholco-Mereprine (Sodium Benzoate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Pholco-Mereprine (Sodium Benzoate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Pholco-Mereprine (Sodium Benzoate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Pholco-Mereprine (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Pholco-Mereprine (Sodium Benzoate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Pholco-Mereprine (Sodium Benzoate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Pholco-Mereprine (Sodium Benzoate) nitrite or 1 g/kg Pholco-Mereprine (Sodium Benzoate) thiosulfate alone or in sequence immediately after subcutaneous injection of Pholco-Mereprine (Sodium Benzoate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Pholco-Mereprine (Sodium Benzoate) nitrite and/or 0.5 g/kg Pholco-Mereprine (Sodium Benzoate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Pholco-Mereprine (Sodium Benzoate) cyanide required to cause death, and when administered together, Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Pholco-Mereprine (Sodium Benzoate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Pholco-Mereprine (Sodium Benzoate) nitrite and Pholco-Mereprine (Sodium Benzoate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Pholco-Mereprine (Sodium Benzoate) nitrite, with or without Pholco-Mereprine (Sodium Benzoate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Pholco-Mereprine (Sodium Benzoate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Pholco-Mereprine (Sodium Benzoate) thiosulfate report its use in conjunction with Pholco-Mereprine (Sodium Benzoate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Pholco-Mereprine (Sodium Benzoate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Pholco-Mereprine (Sodium Benzoate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Pholco-Mereprine (Sodium Benzoate) nitrite injection 30 mg/mL (containing 300 mg of Pholco-Mereprine (Sodium Benzoate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Pholco-Mereprine (Sodium Benzoate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Pholco-Mereprine Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Pholco-Mereprine (Sodium Benzoate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Pholco-Mereprine (Sodium Benzoate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton