Mercodol with Decapryn

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
• Mercodol with Decapryn (Doxylamine Succinate) reviews

1 INDICATIONS AND USAGE

Mercodol with Decapryn (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

Mercodol with Decapryn (Doxylamine Succinate) has not been studied in women with hyperemesis gravidarum.

Mercodol with Decapryn (Doxylamine Succinate) is a fixed dose combination drug product of Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) tablets.

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

3 DOSAGE FORMS AND STRENGTHS

Mercodol with Decapryn (Doxylamine Succinate) delayed-release tablets are white, round, film coated tablets containing 10 mg Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. (3)

4 CONTRAINDICATIONS

Mercodol with Decapryn (Doxylamine Succinate) is contraindicated in women with any of the following conditions:

• Known hypersensitivity to Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) .

• Known hypersensitivity to Mercodol with Decapryn (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 Mercodol with Decapryn 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

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

Mercodol with Decapryn (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

Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) with CNS depressants including alcohol

The most common adverse reaction with Mercodol with Decapryn (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 medicalinfoMercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) is not recommended.

7.2 Drug-Food Interactions

A food-effect study demonstrated that the delay in the onset of action of Mercodol with Decapryn (Doxylamine Succinate) may be further delayed, and a reduction in absorption may occur when tablets are taken with food . Therefore, Mercodol with Decapryn (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. Mercodol with Decapryn is intended for use in pregnant women. (8.1)

8.1 Pregnancy

Pregnancy Category A

Mercodol with Decapryn (Doxylamine Succinate) is intended for use in pregnant women.

The combination of Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

Animal Data

The effects of Mercodol with Decapryn (Doxylamine Succinate) succinate and pyridoxine hydrochloride on embryofetal development have been studied in rats and monkeys.

Once daily treatment of pregnant rats with Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn.

The molecular weight of Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) succinate through breast milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) in children under 18 years of age have not been established.

Fatalities have been reported from Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) succinate. However, there is no correlation between the amount of Mercodol with Decapryn (Doxylamine Succinate) ingested, the Mercodol with Decapryn (Doxylamine Succinate) plasma level and clinical symptomatology.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Mercodol with Decapryn 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, Mercodol with Decapryn (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

Mercodol with Decapryn (Doxylamine Succinate) (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, film-coated, delayed-release tablets containing 10 mg of Mercodol with Decapryn (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.

Mercodol with Decapryn (Doxylamine Succinate) Succinate

Mercodol with Decapryn (Doxylamine Succinate) succinate is classified as an antihistamine. The chemical name for Mercodol with Decapryn (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:

Mercodol with Decapryn (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 Mercodol with Decapryn is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of Mercodol with Decapryn (Doxylamine Succinate) has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for Mercodol with Decapryn (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 Mercodol with Decapryn (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.

Mercodol with Decapryn (Doxylamine Succinate) and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The C_max of Mercodol with Decapryn (Doxylamine Succinate) and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.

Multiple-dose administration of Mercodol with Decapryn (Doxylamine Succinate) results in increased concentrations of Mercodol with Decapryn (Doxylamine Succinate) as well as increases in Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) and pyridoxine. This delay is associated with a lower peak concentration of Mercodol with Decapryn (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

Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate), N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

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

Table 5 – Terminal Elimination Half-Life (T_1/2el) for Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) succinate. Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) or placebo. Two tablets of Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (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

Mercodol with Decapryn 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 Mercodol with Decapryn (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman. Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) until cleared to do so.

Inform women of the importance of not taking Mercodol with Decapryn (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.

Mercodol with Decapryn (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

Mercodol with Decapryn (Doxylamine Succinate) (dye-CLEE-gis)

(doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets

What is Mercodol with Decapryn (Doxylamine Succinate)?

- Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) is safe and effective in children under 18 years of age.

Who should not take Mercodol with Decapryn (Doxylamine Succinate)?

Do not take Mercodol with Decapryn (Doxylamine Succinate) if you:

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

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

Before taking Mercodol with Decapryn (Doxylamine Succinate), tell your healthcare provider about all of your medical conditions, including;

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

- Talk to your healthcare provider about how much Mercodol with Decapryn (Doxylamine Succinate) to take and when to take it.

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

- See the following schedule for the usual way you should start taking Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) on an empty stomach with a glass of water.

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

- If you take too much Mercodol with Decapryn (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 Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate)?

Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate). Severe drowsiness can happen or become worse causing falls or accidents.

These are not all the possible side effects of Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate)?

- Store Mercodol with Decapryn (Doxylamine Succinate) between 68°F to 77°F (20°C to 25°C).

- Keep Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) and all medicines out of the reach of children.

General information about the safe and effective use of Mercodol with Decapryn (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 Mercodol with Decapryn (Doxylamine Succinate) that is written for health professionals. Do not use Mercodol with Decapryn (Doxylamine Succinate) for a condition for which it was not prescribed. Do not give Mercodol with Decapryn (Doxylamine Succinate) to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in Mercodol with Decapryn (Doxylamine Succinate)?

Active ingredient: Mercodol with Decapryn (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

Hydrocodone Bitartrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Medication guide obredon oral solution (oh-brĕ-don oral solution) (hydrocodone bitartrate and guaifenesin) each 5 ml contains hydrocodone bitartrate, usp, 2.5 mg; and guaifenesin, usp, 200 mg. c-ii
• Mercodol with Decapryn (Hydrocodone Bitartrate) reviews

1 INDICATIONS AND USAGE

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is indicated for symptomatic relief of cough and to loosen mucus associated with the common cold.

Important Limitations of Use:

Not indicated for pediatric patients under 18 years of age .

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is a combination product containing an opioid antitussive and expectorant indicated for:

• Symptomatic relief of cough and to loosen mucus associated with the common cold.

Important Limitations of Use:

Not indicated for pediatric patients under 18 years of age. ( 8.4)

2 DOSAGE AND ADMINISTRATION

Adults and adolescents 18 years of age and older: 10 mL every 4 to 6 hours, not to exceed 6 doses in 24 hours. ( 2.1)

Measure Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with an accurate milliliter measuring device. ( 5.10)

2.1 Recommended dosage

Adults and adolescents 18 years of age and older: 10 mL every 4 to 6 hours, not to exceed 6 doses (60 mL) in 24 hours.

Administer Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution by the oral route only. Measure Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with an accurate milliliter measuring device. Do not use a household teaspoon to measure the dose .

3 DOSAGE FORMS AND STRENGTHS

Oral Solution:

Each 5 mL contains Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, USP, 2.5 mg; and guaifenesin, USP, 200 mg .

Oral Solution: Each 5 mL contains Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, USP, 2.5 mg; and guaifenesin, USP, 200 mg.( 3)

4 CONTRAINDICATIONS

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is contraindicated in:

• Patients with known hypersensitivity to Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, guaifenesin, or any of the inactive ingredients of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.
• Patients receiving MAOI therapy or within 14 days of stopping such therapy .

• Patients with known hypersensitivity to Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, guaifenesin, or any of the inactive ingredients of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. ( 4)
• Patients receiving monoamine oxidase inhibitor (MAOI) therapy or within 14 days of stopping such therapy. ( 4)

5 WARNINGS AND PRECAUTIONS

• Dose-related respiratory depression: Use with caution.
• Drug Dependence: Prescribe with caution that is appropriate to the use of other opioids. ( 5.3)
• Head injury and increased intracranial pressure: Avoid in patients with head injury, intracranial lesions or increased intracranial pressure. ( 5.4)
• Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring complete mental alertness such as driving or operating machinery. ( 5.5)
• Acute abdominal conditions: Use with caution in patients with acute abdominal conditions. ( 5.6)
• Coexisting conditions: Use with caution in patients with diabetes, thyroid disease, Addison’s disease, prostatic hypertrophy, or urethral stricture, or asthma. ( 5.11)

5.1 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

Concomitant use of opioids, including Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol .

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants .

5.2 Respiratory Depression

Mercodol with Decapryn bitartrate, one of the active ingredients in Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Overdose of Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate in adults has been associated with fatal respiratory depression, and the use of Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate in children less than 6 years of age has been associated with fatal respiratory depression. Exercise caution when administering Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution because of the potential for respiratory depression. If respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride and other supportive measures when indicated .

5.3 Drug Dependence

Mercodol with Decapryn (Hydrocodone Bitartrate) can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. Prescribe and administer Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with the same degree of caution appropriate to the use of other opioid drugs .

5.4 Head Injury and Increased Intracranial Pressure

The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries. The use of Mercodol with Decapryn Oral Solution should be avoided in these patients.

5.5 Activities Requiring Mental Alertness

Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, one of the active ingredients in Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. Concurrent use of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur.

5.6 Acute Abdominal Conditions

Mercodol with Decapryn Oral Solution should be used with caution in patients with acute abdominal conditions since the administration of Mercodol with Decapryn (Hydrocodone Bitartrate) may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with Mercodol with Decapryn (Hydrocodone Bitartrate) may produce paralytic ileus .

5.7 Co-administration with Anticholinergics

The concurrent use of anticholinergics with Mercodol with Decapryn (Hydrocodone Bitartrate) may produce paralytic ileus. Exercise caution when using Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in patients taking anticholinergic medications .

5.8 Co-administration with MAOIs or Tricyclic Antidepressants

Mercodol with Decapryn Oral Solution should not be used in patients receiving MAOI therapy or within 14 days of stopping such therapy. The use of MAOIs or tricyclic antidepressants with Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate may increase the effect of either the antidepressant or Mercodol with Decapryn (Hydrocodone Bitartrate) .

5.9 Persistent Cough

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should not be used in patients with a persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis, or emphysema, or where cough is accompanied by excessive phlegm (mucus).

5.10 Dosing

Patients should be advised to measure Mercodol with Decapryn Oral Solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions . Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose.

5.11 Coexisting Conditions

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should be used with caution in patients with diabetes, thyroid disease, Addison's disease, prostatic hypertrophy or urethral stricture, and asthma.

5.12 Renal Impairment

Mercodol with Decapryn Oral Solution should be used with caution in patients with severe renal impairment.

5.13 Hepatic Impairment

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should be used with caution in patients with severe hepatic impairment .

6 ADVERSE REACTIONS

Use of Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate is associated with the following:

• Respiratory depression
• Drug dependence
• Increased intracranial pressure
• Decreased mental alertness with impaired mental and/or physical abilities
• Paralytic ileus

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 most common adverse reactions experienced by subjects taking a single dose of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in the clinical setting include the following: Central Nervous System: headache, dizziness, sedation (somnolence); Gastrointestinal System: nausea, diarrhea; Cardiovascular System: decreased blood pressure; Vascular System: hot flush.

The most common adverse reactions of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution include:

Dizziness, headache, sedation, nausea, and decreased blood pressure. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact ABER Pharmaceuticals, LLC. at tel: 1-855-461-5102; www.obredon.com or FDA at 1-800-FDA-1088; www.fda.gov/medwatch.

7 DRUG INTERACTIONS

No specific interaction studies have been conducted with Mercodol with Decapryn Oral Solution.

• Opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol): Avoid using with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution; may exhibit additive CNS depression. ( 7.1)
• MAO inhibitors (MAOIs) or tricyclic antidepressants: Do not use. May increase the effect of either the antidepressant or Mercodol with Decapryn (Hydrocodone Bitartrate). ( 7.2)
• Anticholinergic drugs: Use with caution in order to avoid paralytic ileus and excessive anticholinergic effects. ( 7.3)

7.1 Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided .

7.2 MAO Inhibitors or Tricyclic Antidepressants

Do not prescribe Mercodol with Decapryn Oral Solution if the patient is taking a prescription MAOI (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping a MAOI drug. The use of MAOIs or tricyclic antidepressants with Mercodol with Decapryn (Hydrocodone Bitartrate) preparations may increase the effect of either the antidepressant or Mercodol with Decapryn (Hydrocodone Bitartrate) .

7.3 Anticholinergic Drugs

Mercodol with Decapryn (Hydrocodone Bitartrate) should be administered cautiously to persons receiving anticholinergic drugs in order to avoid paralytic ileus and excessive anticholinergic effects .

8 USE IN SPECIFIC POPULATIONS

• Renal Impairment: Use with caution in patients with severe renal impairment.
• Hepatic Impairment: Use with caution in patients with severe hepatic impairment. ( 8.7)

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well controlled studies of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in pregnant women. Reproductive toxicity studies have not been conducted with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution; however, studies are available with an individual active ingredient or related active ingredient. Mercodol with Decapryn (Hydrocodone Bitartrate) was teratogenic in hamsters. Codeine, an opiate related to Mercodol with Decapryn (Hydrocodone Bitartrate), increased resorptions and decreased fetal weight in rats. Because animal reproduction studies are not always predictive of human response, Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Mercodol with Decapryn (Hydrocodone Bitartrate):

Mercodol with Decapryn (Hydrocodone Bitartrate) has been shown to be teratogenic in hamsters when given in a dose approximately 27 times the maximum recommended human daily dose (MRHDD) (on a mg/m ² basis at a single subcutaneous dose of 102 mg/kg on gestation day 8). Reproductive toxicology studies were also conducted with codeine, an opiate related to Mercodol with Decapryn (Hydrocodone Bitartrate). In a study in which pregnant rats were dosed throughout organogenesis, a dose of codeine approximately 40 times the MRHDD of Mercodol with Decapryn (Hydrocodone Bitartrate) (on a mg/m ² basis at an oral dose of 120 mg/kg/day of codeine) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity. In studies in which rabbits and mice were dosed throughout organogenesis, doses of codeine up to approximately 20 and 100 times, respectively, the MRHDD of Mercodol with Decapryn (Hydrocodone Bitartrate) (on a mg/m ² basis at oral doses of 30 and 600 mg/kg/day, respectively), produced no adverse developmental effects.

Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

8.2 Labor and Delivery

As with all opioids, administration of Mercodol with Decapryn Oral Solution to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

8.3 Nursing Mothers

Caution should be exercised when Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is administered to nursing mothers. Mercodol with Decapryn (Hydrocodone Bitartrate) is known to be excreted in human milk. No studies have been performed to determine if guaifenesin is excreted into breastmilk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of Mercodol with Decapryn Oral Solution in pediatric patients under 18 years of age has not been established. The use of Mercodol with Decapryn (Hydrocodone Bitartrate) in children less than 6 years of age is associated with fatal respiratory depression .

8.5 Geriatric Use

Clinical studies have not been conducted with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in geriatric populations. Other reported clinical experience with the individual active ingredients of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution has not identified differences in responses between the elderly and patients younger than 65 years of age. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Mercodol with Decapryn Oral Solution should be given with caution in patients with severe impairment of renal function.

8.7 Hepatic Impairment

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should be given with caution in patients with severe impairment of hepatic function.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Mercodol with Decapryn Oral Solution is a Schedule II controlled prescription containing Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate and should be prescribed and administered with caution.

9.2 Abuse

Mercodol with Decapryn (Hydrocodone Bitartrate) can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs.

Abuse of guaifenesin has been linked to the formation of kidney stones composed of the major metabolite β-(2-methoxyphenoxy) lactic acid.

9.3 Dependence

Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution should be prescribed and administered with caution.

Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

10 OVERDOSAGE

No human overdosage data are available for Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.

Mercodol with Decapryn (Hydrocodone Bitartrate):

Overdosage with Mercodol with Decapryn (Hydrocodone Bitartrate) is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, dizziness, ringing in the ears, confusion, blurred vision, eye problems, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdose, apnea, circulatory collapse, cardiac arrest and death may occur.

Guaifenesin:

Overdosage with guaifenesin can cause depression of the central nervous system. While present in polypharmacy overdoses, one case of overdose with only significant levels of guaifenesin has been reported. Symptoms included slurred speech, shallow respirations, reduced heart rate with rhythm sinus bradycardia, followed by asystole.

Treatment of overdosage consists of discontinuation of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution together with institution of appropriate therapy. Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression which may result from overdosage or unusual sensitivity to opioids including Mercodol with Decapryn (Hydrocodone Bitartrate). Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug.

11 DESCRIPTION

Mercodol with Decapryn Oral Solution contains Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate (a centrally-acting opioid antitussive) and guaifenesin (an expectorant).

Each 5 mL dose of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution contains: Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, USP, 2.5 mg; and guaifenesin, USP, 200 mg.

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution also contains: artificial raspberry flavor, citric acid, glycerin, methylparaben, potassium citrate, potassium sorbate, propylene glycol, propylparaben, purified water, and saccharin sodium.

11.1 Mercodol with Decapryn (Hydrocodone Bitartrate) Bitartrate

Mercodol with Decapryn (Hydrocodone Bitartrate) Bitartrate is a centrally-acting opioid antitussive and analgesic. It is affected by light and occurs as fine white crystals or crystalline powder which is derived from the opium alkaloid, thebaine. Its chemical name is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It is also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5); and may be represented by the following structural formula:

C ₁₈H ₂₁NO ₃ - C ₄H ₆O ₆ - 2½H ₂O MW= 494.50

HCB Chemical Structure

11.2 Guaifenesin

Guaifenesin is an expectorant and occurs as a white powder. Its chemical name is 3-(2-methoxyphenoxy)-1,2- propanediol, and may be represented by the following structural formula:

C ₁₀H ₁₄O ₄ MW= 198.22

GFN Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mercodol with Decapryn is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of codeine. The precise mechanism of action of Mercodol with Decapryn (Hydrocodone Bitartrate) and other opiates is not known; however, Mercodol with Decapryn (Hydrocodone Bitartrate) is believed to act directly on the cough center. In excessive doses, Mercodol with Decapryn (Hydrocodone Bitartrate) will depress respiration. Mercodol with Decapryn (Hydrocodone Bitartrate) can produce miosis, euphoria, and physical and physiological dependence.

Guaifenesin is an expectorant the action of which promotes or facilitates the removal of secretions from the respiratory tract. The precise mechanism of action of guaifenesin is not known; however, it is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. In turn, this may increase the efficiency of the cough reflex and facilitate removal of the secretions.

12.3 Pharmacokinetics

Systemic exposure (in terms of peak plasma concentrations and area under plasma concentration versus time curve) of Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate and guaifenesin after single dose administration of 10 mL Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution are equivalent to respective reference solutions of 5 mL Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate (5 mg/5 mL), and 10 mL guaifenesin (200 mg/5 mL).

Mercodol with Decapryn (Hydrocodone Bitartrate): Following a single 10 mL oral dose of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution administered to 36 healthy adults (19-74 years), the geometric mean C _max and AUC _0-inf for Mercodol with Decapryn (Hydrocodone Bitartrate) were 12.6 ng/ml and 80.9 ng·hr/ml, respectively. The median time to maximum concentration for Mercodol with Decapryn (Hydrocodone Bitartrate) was about 1.25 hours. Food has no significant effect on the extent of absorption of Mercodol with Decapryn (Hydrocodone Bitartrate). The mean plasma half-life of Mercodol with Decapryn (Hydrocodone Bitartrate) is approximately 5 hours.

Guaifenesin: Following a single 10 mL oral dose of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution administered to 57 healthy adults (19-74 years), the geometric mean Cmax and AUC0-inf for guaifenesin were 3.7 mcg/ml and 4.2 mcg·hr/ml, respectively. The median time to maximum concentration was about 20 minutes. The effect of food on guaifenesin systemic exposure is not considered to be clinically meaningful. The mean plasma half-life of guaifenesin is approximately 1 hour.

Drug interactions

When guaifenesin and Mercodol with Decapryn (Hydrocodone Bitartrate) were administered in combination, the pharmacokinetics for each component were similar to those observed when each component was administered separately.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution; however, published information is available for the individual active ingredients or related active ingredients.

Mercodol with Decapryn (Hydrocodone Bitartrate):

Carcinogenicity studies were conducted with codeine, an opiate related to Mercodol with Decapryn (Hydrocodone Bitartrate). In 2 year studies in F344/N rats and B6C3F1 mice, codeine showed no evidence of tumorigenicity at dietary doses up to 70 and 400 mg/kg/day, respectively (approximately 23 and 65 times, respectively, the MRHDD of Mercodol with Decapryn (Hydrocodone Bitartrate) on a mg/m ² basis).

Guaifenesin:

Carcinogenicity, genotoxicity, or reproductive toxicology studies have not been conducted with guaifenesin

14 CLINICAL STUDIES

Efficacy studies were not conducted with Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. Efficacy of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is based on demonstration of bioequivalence to the individual comparator products .

16 HOW SUPPLIED/STORAGE AND HANDLING

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is supplied as a clear, raspberry flavored liquid containing 2.5 mg Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate and 200 mg guaifenesin in each 5 mL. It is available in:

White HDPE bottles of 16 fl oz. (473 mL): NDC 69166-523-16 (raspberry flavored)

White HDPE bottles of 4 fl oz. (118 mL): NDC 69166-523-04 (raspberry flavored)

Store solution at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

Overdosage

Advise patients not to increase the dose or dosing frequency of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution because serious adverse events such as respiratory depression may occur with overdosage .

Dosing

Advise patients to measure Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is measured. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose .

Interactions with Benzodiazepines and Other Central Nervous System Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol.

Because of this risk, patients should avoid concomitant use of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with benzodiazepines or other CNS depressants, including alcohol .

Activities Requiring Mental Alertness

Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution may produce marked drowsiness .

Drug Dependence

Caution patients that Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution contains Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate and can produce drug dependence .

For Medical Information

Contact Medical Affairs Department

Phone: 1-855-461-5102

Manufactured for:

Accelis Pharma

East Windsor, NJ 08520

ACELLIS logo

MEDICATION GUIDE

Mercodol with Decapryn Oral Solution (Oh-brĕ-don Oral Solution)

(hydrocodone bitartrate and guaifenesin) Each 5 mL contains Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate, USP, 2.5 mg; and guaifenesin, USP, 200 mg. C-II

What is the most important information I should know about Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with benzodiazepines, or other central nervous system depressants, including alcohol can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.
• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution can cause you to be drowsy. Do not drive a car or operate machinery until you know how Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution affects you. Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution can slow your thinking and motor skills, and may affect your vision.
• Women who breastfeed should talk to their healthcare provider before taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.
• Call your healthcare provider or get emergency medical help right away if anyone taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution has any of the symptoms below:
  • increased sleepiness
  • confusion
  • difficulty breathing
  • shallow breathing
  • limpness
  • your baby has difficulty breastfeeding
• Keep Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in a safe place away from children. Accidental use by a child is a medical emergency and can cause death. If a child accidentally takes Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, get emergency medical help right away.
• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution can cause serious side effects, including death.
• Take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution exactly as prescribed by your healthcare provider. If you take the wrong dose of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, you could overdose and die.
• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is not for children under 18 years of age.

What is Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is a prescription medicine used to treat a cough and to loosen mucus associated with the common cold, in patients 18 years and older. Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution contains two medicines, Mercodol with Decapryn (Hydrocodone Bitartrate) and guaifenesin. Mercodol with Decapryn (Hydrocodone Bitartrate) is a narcotic cough suppressant. Guaifenesin is an expectorant.
• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is a federal controlled substance (C-II) because it contains Mercodol with Decapryn (Hydrocodone Bitartrate) that can be abused or lead to dependence. Keep Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution in a safe place to prevent misuse and abuse. Selling or giving away Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is not for children under 18 years of age. It is not known if Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution is safe and effective in children.

Who should not take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Do not take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution if you are allergic to any of the ingredients in Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. See the end of this Medication Guide for a complete list of ingredients. You may have an increased risk of having an allergic reaction to Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution if you are allergic to certain other opioid medicines.
• Do not take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution if you take a medicine for depression called a Monoamine Oxidase Inhibitor (MAOI)
  • Do not take an MAOI within 14 days after you stop taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.
  • Do not start Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution if you stopped taking an MAOI in the last 14 days.

Before you take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, tell your healthcare provider about all of your medical conditions, including if you:

• • have a drug dependence
  • have lung or breathing problems
  • have had a head injury
  • have pain in your stomach-area (abdomen)
  • have a history of severe or persistent cough
  • have prostate problems
  • have problems with your urinary tract(urethral stricture)
  • plan to have surgery
  • drink alcohol
  • have kidney or liver problems
  • have diabetes
  • have thyroid problems, such as hypothyroidism
  • are pregnant or plan to become pregnant. It is not known if Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution will harm your unborn baby. You and your healthcare provider should decide if you should take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution while you are pregnant.
  • are breastfeeding or plan to breastfeed. It is not known if Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution passes into your breast milk. You and your healthcare provider should decide if you will take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution or breastfeed. You should not do both.

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

Taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution with certain other medicines can cause side effects or affect how well Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

Especially tell your healthcare provider if you:

• take pain medicines such as narcotics
• take cold or allergy medicines that contain antihistamines or cough suppressants
• take medicines for mental illness (anti-psychotics, anti-anxiety)
• drink alcohol
• take medicines for depression, including monoamine oxidase inhibitors (MAOIs) and tricyclics
• The use of MAOIs or tricyclic antidepressants with Mercodol with Decapryn (Hydrocodone Bitartrate) bitartrate may increase the effect of either the antidepressant or Mercodol with Decapryn (Hydrocodone Bitartrate).

How should I take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution to take and when to take it. Do not change your dose without talking to your healthcare provider.
• Administer Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution by the oral route only.
• Ask your pharmacist to give you a measuring device to help you measure the correct amount of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. Do not use a household teaspoon to measure your medicine. You may accidently take too much.
• If you take too much Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution can cause you to be drowsy. Do not drive a car or operate machinery while you take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution until you know how it affects you.
• Avoid drinking alcohol while taking Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution. Drinking alcohol can increase your chances of having serious side effects.

What are the possible side effects of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution may cause serious side effects, including:

• See “What is the most important information I should know about Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?”
• breathing problems (respiratory depression) which can lead to death. Call your healthcare provider or get emergency treatment right away if you are sleeping more than usual, have shallow or slow breathing, or confusion.
• Physical dependence or abuse. Take Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution exactly as your healthcare provider tells you to take it. Stopping Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution suddenly could cause withdrawal symptoms.
• Bowel problems including constipation or stomach pain.

The most common side effects of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution include:

• Sleepiness
• Confusion
• nausea and vomiting
• difficulty urinating
• trouble breathing

These are not all the possible side effects of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.

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 Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

• Store Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution at room temperature between 68°F to 77°F (20°C to 25°C).
• Safely throw away medicine that is out of date or no longer needed.
• Keep Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution and all medicines out of the reach of children.

General information about the safe and effective use of Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution for a condition for which it was not prescribed. Do not give Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution that is written for health professionals.

What are the ingredients in Mercodol with Decapryn (Hydrocodone Bitartrate) Oral Solution?

Active ingredients: Mercodol with Decapryn (Hydrocodone Bitartrate) Bitartrate and Guaifenesin

Inactive ingredients: artificial raspberry flavor, citric acid, glycerin, methylparaben, potassium citrate, potassium sorbate, propylene glycol, propylparaben, purified water, and saccharin sodium

Manufactured for:

Accelis Pharma, East Windsor, NJ 08520

For more information, go to www.obredon.com or call 1-855-461-5102.

This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: 09/2016

Sodium Citrate:

• 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
• Mercodol with Decapryn (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

Mercodol with Decapryn nitrite is indicated for sequential use with Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) Nitrite Injection is indicated for sequential use with Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn 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, Mercodol with Decapryn (Sodium Citrate) Nitrite Injection and Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) thiosulfate, simultaneously with Mercodol with Decapryn (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Mercodol with Decapryn (Sodium Citrate) thiosulfate, with Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite, followed by Mercodol with Decapryn (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate.

Mercodol with Decapryn (Sodium Citrate) nitrite injection and Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) nitrite should be administered first, followed immediately by Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn 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 Mercodol with Decapryn (Sodium Citrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Mercodol with Decapryn (Sodium Citrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Mercodol with Decapryn (Sodium Citrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Mercodol with Decapryn (Sodium Citrate) thiosulfate and Mercodol with Decapryn (Sodium Citrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Mercodol with Decapryn (Sodium Citrate) Nitrite Injection consists of:

• One vial of Mercodol with Decapryn (Sodium Citrate) 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: Mercodol with Decapryn 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 Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Mercodol with Decapryn (Sodium Citrate) nitrite whenever possible. When Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite administered to an adult. Mercodol with Decapryn (Sodium Citrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Mercodol with Decapryn 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn 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 Mercodol with Decapryn (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite.

The medical literature has reported the following adverse events in association with Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Mercodol with Decapryn 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. Mercodol with Decapryn (Sodium Citrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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, Mercodol with Decapryn (Sodium Citrate) 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, Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Mercodol with Decapryn (Sodium Citrate) 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, Mercodol with Decapryn 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 Mercodol with Decapryn (Sodium Citrate) nitrite is excreted in human milk. Because Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Mercodol with Decapryn (Sodium Citrate) nitrite. In studies conducted with Long-Evans rats, Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn nitrite in conjunction with Mercodol with Decapryn (Sodium Citrate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Mercodol with Decapryn (Sodium Citrate) 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.

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) nitrite has the chemical name nitrous acid Mercodol with Decapryn (Sodium Citrate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Mercodol with Decapryn (Sodium Citrate) Nitrite

Mercodol with Decapryn (Sodium Citrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Mercodol with Decapryn (Sodium Citrate) nitrite injection.

Mercodol with Decapryn (Sodium Citrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Mercodol with Decapryn (Sodium Citrate) nitrite in 10 mL solution (30 mg/mL). Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Mercodol with Decapryn (Sodium Citrate) Nitrite

Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite. It has been suggested that Mercodol with Decapryn (Sodium Citrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Mercodol with Decapryn (Sodium Citrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) Nitrite

When 4 mg/kg Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Mercodol with Decapryn (Sodium Citrate) Nitrite

Mercodol with Decapryn (Sodium Citrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Mercodol with Decapryn (Sodium Citrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Mercodol with Decapryn (Sodium Citrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) 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. Mercodol with Decapryn (Sodium Citrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Mercodol with Decapryn (Sodium Citrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Mercodol with Decapryn (Sodium Citrate) nitrite or 1 g/kg Mercodol with Decapryn (Sodium Citrate) thiosulfate alone or in sequence immediately after subcutaneous injection of Mercodol with Decapryn (Sodium Citrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Mercodol with Decapryn (Sodium Citrate) nitrite and/or 0.5 g/kg Mercodol with Decapryn (Sodium Citrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Mercodol with Decapryn (Sodium Citrate) cyanide required to cause death, and when administered together, Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) nitrite and Mercodol with Decapryn (Sodium Citrate) thiosulfate in the treatment of cyanide poisoning.

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

14 CLINICAL STUDIES

The human data supporting the use of Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) thiosulfate report its use in conjunction with Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) 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 Mercodol with Decapryn (Sodium Citrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Mercodol with Decapryn (Sodium Citrate) nitrite injection 30 mg/mL (containing 300 mg of Mercodol with Decapryn (Sodium Citrate) 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: Mercodol with Decapryn (Sodium Citrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Mercodol with Decapryn 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

Mercodol with Decapryn (Sodium Citrate) 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

Mercodol with Decapryn (Sodium Citrate) 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