Benadryl DMP

Ammonium Chloride:

• Indications and usage
• Contraindications
• Warning
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Benadryl DMP (Ammonium Chloride) reviews

INDICATIONS AND USAGE

Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% is indicated for the treatment of dry, scaly skin (xerosis) and ichthyosis vulgaris, and for the temporary relief of itching associated with these conditions.

CONTRAINDICATIONS

Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% is contraindicated in those patients with a history of hypersensitivity to any of the label ingredients.

WARNING

Sun exposure (natural or artificial sunlight) to areas of the skin treated with Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% should be minimized or avoided (see PRECAUTIONS). The use of Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% should be discontinued if any hypersensitivity is observed.

PRECAUTIONS

General -

For external use only. Stinging or burning may occur when applied to skin with fissures, erosions, or that is otherwise abraded. Caution is advised when used on the face because of the potential for irritation. The potential for post-inflammatory hypo- or hyperpigmentation has not been studied.

Information for Patients

Patients using Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% should receive the following information and instructions:

• This medication is to be used as directed by the physician, and should not be used for any disorder other than for which it was prescribed. It is for external use only. Avoid contact with eyes, lips, or mucous membranes.
• Patients should minimize or avoid use of this product on areas of the skin that may be exposed to natural or artificial sunlight, including the face. If sun exposure is unavoidable, clothing should be worn to protect the skin.
• This medication may cause transient stinging or burning when applied to skin with fissures, erosions, or abrasions (for example, after shaving the legs).
• If the skin condition worsens with treatment, the medication should be promptly discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility -

The topical treatment of CD-1 mice with 12%, 21% or 30% Benadryl DMP lactate formulations for two-years did not produce a significant increase in dermal or systemic tumors in the absence of increased exposure to ultraviolet radiation. The maximum systemic exposure of the mice in this study was 0.7 times the maximum possible systemic exposure in humans. However, a long-term photocarcinogenicity study in hairless albino mice suggested that topically applied 12% Benadryl DMP (Ammonium Chloride) lactate formulations enhanced the rate of ultraviolet light-induced skin tumor formation.

The mutagenic potential of Benadryl DMP (Ammonium Chloride) lactate formulations was evaluated in the Ames assay and in the mouse in vivo micronucleus assay, both of which were negative.

In dermal Segment I and III studies with Benadryl DMP (Ammonium Chloride) lactate formulations there were no effects observed in fertility or pre- or postnatal development parameters in rats at dose levels of 300 mg/kg/day (1800 mg/m²/day), approximately 0.4 times the human topical dose.

Pregnancy:

Teratogenic effects:

Pregnancy Category B -

Animal reproduction studies have been performed in rats and rabbits at doses up to 0.7 and 1.5 times the human dose, respectively and have revealed no evidence of impaired fertility or harm to the fetus due to Benadryl DMP (Ammonium Chloride) lactate formulations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Benadryl DMP (Ammonium Chloride) Lactate Lotion, 12% should be used during pregnancy only if clearly needed.

Nursing Mothers -

Although lactic acid is a normal constituent of blood and tissues, it is not known to what extent this drug affects normal lactic acid levels in human milk. Because many drugs are excreted in human milk, caution should be exercised when Benadryl DMP (Ammonium Chloride) lactate is administered to a nursing woman.

Pediatric Use -

Safety and effectiveness of Benadryl DMP lactate have been demonstrated in infants and children. No unusual toxic effects were reported.

Geriatric Use -

Clinical studies of Benadryl DMP (Ammonium Chloride) lactate lotion, 12% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious.

ADVERSE REACTIONS

The most frequent adverse experiences in patients with xerosis are transient stinging (1 in 30 patients), burning (1 in 30 patients), erythema (1 in 50 patients) and peeling (1 in 60 patients). Other adverse reactions which occur less frequently are irritation, eczema, petechiae, dryness, and hyperpigmentation. Due to the more severe initial skin conditions associated with ichthyosis, there was a higher incidence of transient stinging, burning and erythema (each occurring in 1 in 10 patients).

OVERDOSAGE

The oral administration of Benadryl DMP (Ammonium Chloride) lactate to rats and mice showed this drug to be practically non-toxic (LD₅₀>15 mL/kg).

DOSAGE AND ADMINISTRATION

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.

HOW SUPPLIED

Benadryl DMP Lactate Lotion, 12% is available as follows:

225 g bottle (NDC 45802-419-54)

400 g bottle (NDC 45802-419-26)

STORAGE

Store at 20-25°C (68-77°F).

Manufactured By Perrigo, Bronx, NY 10457

Distributed By Perrigo, Allegan, MI 49010

0K5A7 RC F6

Rev 01-17

Dextromethorphan Hydrobromide:

• Pharmacological action
• Pharmacokinetics
• Why is Benadryl DMP prescribed?
• Dosage and administration
• Benadryl DMP (Dextromethorphan Hydrobromide) side effects, adverse reactions
• Benadryl DMP contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Benadryl DMP drug interactions
• Benadryl DMP in case of emergency / overdose
• Benadryl DMP (Dextromethorphan Hydrobromide) reviews

Pharmacological action

Benadryl DMP is an antitussive medication. Inhibiting the excitability of the cough center this medicine suppresses the cough of any origin. Benadryl DMP (Dextromethorphan Hydrobromide) has not addiction effects and it has no analgesic and hypnotic action. Benadryl DMP (Dextromethorphan Hydrobromide) starts to act after 10-30 minutes after oral administration, the duration of therapeutic action: 5-6 hours for adults and 6-9 hours for children. Benadryl DMP (Dextromethorphan Hydrobromide) is an optical isomer of levomethorphan which is similar to morphine. Due to optical isomerism this drug has no opioid effects. Benadryl DMP (Dextromethorphan Hydrobromide) used mainly for replacement of codeine as a cough suppressant. In addition to the cough suppressant this medication is used in medicine for diagnostic purposes and may be useful in various cases - from seizures to heroin addiction treatment, some chronic neurodegenerative diseases. These include amyotrophic lateral sclerosis (ALS) (Charcot's disease), disease of "mad cow and other prion diseases. Benadryl DMP (Dextromethorphan Hydrobromide) has also been used for the treatment of mental retardation, Parkinson's disease, in the treatment of lung and other cancers and to prevent tissue rejection in transplantation because of the (poorly known) effects of sigma ligands on tumor cells and immune system.

Pharmacokinetics

After oral administration Benadryl DMP (Dextromethorphan Hydrobromide) is completely absorbed from the gastrointestinal tract. C_max of Benadryl DMP (Dextromethorphan Hydrobromide) in plasma is reached after 2 h. This medication biotransformes in the liver. Up to 45% of this drug is excreted by kidneys and there was considerable individual variation in rates of excretion of individual metabolites.

Why is Benadryl DMP prescribed?

Dry cough of different etiology.

Dosage and administration

For adults and children over 12 years Benadryl DMP prescribed on 15 mg 4 times / day, children aged 6 years - 7.5 mg 4 times / day.

Benadryl DMP (Dextromethorphan Hydrobromide) side effects, adverse reactions

Drowsiness, nausea, dizziness.

Benadryl DMP contraindications

Bronchial asthma, bronchitis, simultaneous reception of mucolytic.

Using during pregnancy and breastfeeding

During pregnancy and lactation (breastfeeding) Benadryl DMP (Dextromethorphan Hydrobromide) prescribed with caution, only in cases where the expected therapeutic effect for the mother outweighs the potential risk to the fetus or child.

Special instructions

With carefully administered Benadryl DMP (Dextromethorphan Hydrobromide) with impaired liver function.

Benadryl DMP drug interactions

MAO inhibitors (including furazolidone, procarbazine, selegiline) when administered simultaneous with Benadryl DMP (Dextromethorphan Hydrobromide) may cause adrenergic crisis, collapse, coma, dizziness, agitation, increased blood pressure, hyperpyrexia, intracranial hemorrhage, lethargy, nausea, cramps, tremor. In combination with tricyclic antidepressants (amitriptyline, etc.) Benadryl DMP (Dextromethorphan Hydrobromide) may appeal serotonin syndrome and possible subsequent death. Amiodarone, fluoxetine, quinidine, inhibiting system cytochrome P450, may increase the drug concentration in the blood. Tobacco smoke can lead to increased secretion of glands in the background of inhibition of cough reflex. Some inhibitors of CYP450 (such as quinidine) increase and extended effects of this medicine.

Benadryl DMP in case of emergency / overdose

Symptoms: excitement, dizziness, respiratory depression, impaired consciousness, decreased blood pressure, tachycardia, muscle hypertonicity, ataxia.

Treatment: mechanical ventilation, symptomatic agents.

Diphenhydramine Hydrochloride:

• Pharmacological action
• Pharmacokinetics
• Why is Benadryl DMP Xepa-Soul Pattinson prescribed?
• Dosage and administration
• Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson side effects, adverse reactions
• Benadryl DMP Xepa-Soul Pattinson contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Precautionary measures
• Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson drug interactions
• Benadryl DMP Xepa-Soul Pattinson in case of emergency / overdose
• Benadryl DMP (Diphenhydramine Hydrochloride) reviews

Pharmacological action

Benadryl DMP Xepa-Soul Pattinson is a blocker of histamine H1-receptors. It has antiallergic activity, has a local anesthetic, antispasmodic and mild ganglion blocking action.

When Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson administered orally Benadryl DMP (Diphenhydramine Hydrochloride) has a sedative and hypnotic effects, has a moderate antiemetic effect and has a central holinoliticheskoy activity.

When applied externally it has antiallergic effect.

Pharmacokinetics

Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson is rapidly absorbed from the gastrointestinal tract. Bioavailability is 50%. C_max is achieved after 20-40 min (in the greatest concentration is determined in the lungs, spleen, kidneys, liver, brain and muscles). Binding to plasma proteins - 98-99%. Penetrates through the BBB. Metabolised mainly in the liver, partly - in the lungs and kidneys. T1/2 is 4-10 hours. Within one day completely removed kidneys as metabolites conjugated to glucuronic acid. Significant quantities are derived from milk and can cause sedation in infants (may be a paradoxical reaction characterized by hyperexcitability).

Why is Benadryl DMP Xepa-Soul Pattinson prescribed?

Allergic reactions (urticaria, hay fever, angioedema), allergic conjunctivitis, vasomotor rhinitis, Henoch-Schonlein purpura, serum sickness, itchy dermatitis, sleep disorders (monotherapy or in combination with drugs), chorea, sea and air sickness, vomiting in pregnancy, Meniere's syndrome, premedication.

Dosage and administration

Oral, IV, IM, rectal, topical, intranasal, in the conjunctival sac. Oral dose of Benadryl DMP Xepa-Soul Pattinson for adults is 30-50 mg 1-3 times / day. The treatment course is 10-15 days. As soporific - 50 mg at bedtime. IM in doses of 50-250 mg; IV in drip - 20-50 mg. When oral administered single dose for children under 1 year - 2-5 mg; from 2 to 5 years - 5-15 mg; of 6 to 12 years - 15-30 mg. Externally applied 1-2 times / day.

Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson side effects, adverse reactions

Possible: a short-term numbness in the oral mucosa, drowsiness, weakness, decrease in psychomotor speed of reaction in children may be a paradoxical development of insomnia, irritability, and euphoria.

Rarely: dizziness, headache, dry mouth, nausea, photosensitivity, paresis of accommodation, poor coordination of movements, tremor.

Benadryl DMP Xepa-Soul Pattinson contraindications

Closure glaucoma, prostatic hypertrophy, stenosing peptic ulcer, stenosis of the bladder neck, bronchial asthma, epilepsy, hypersensitivity to Benadryl DMP (Diphenhydramine Hydrochloride).

Using during pregnancy and breastfeeding

During pregnancy and lactation, Benadryl DMP (Diphenhydramine Hydrochloride) used with caution, according to strict indications, when the expected therapeutic effect for the mother outweighs the potential risk to the fetus or infant.

Special instructions

With careful use Benadryl DMP (Diphenhydramine Hydrochloride) during pregnancy and lactation.

During the period of treatment with Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson should not be exposed to solar radiation should be avoided alcohol.

Used with caution in patients involved in potentially dangerous activities requiring attention and rapid psychomotor reactions.

Precautionary measures

Benadryl DMP Xepa-Soul Pattinson is not recommended for SC injection. Since Benadryl DMP (Diphenhydramine Hydrochloride) has atropinopodobnym action should be cautious in its use: patients with recent respiratory infection in history (including asthma), increased intraocular pressure in hyperthyroidism, cardiovascular system, hypotension. Antihistamines drugs can reduce mental alertness as well as in adults and children and also cause agitation and hallucinations, convulsions and death in infants and children, especially in overdose. Precautions apply at age 60 and older because more likely to develop dizziness, sedation and hypotension. During treatment with Benadryl DMP (Diphenhydramine Hydrochloride) should avoid sun exposure. Should not be used during the drivers of vehicles and people, trade is connected with increased concentration. In the period of treatment should avoid drinking alcoholic beverages.

Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson drug interactions

When Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson applied simultaneously increases the effects of ethanol and drugs that depress the central nervous system.

With simultaneous use of Benadryl DMP (Diphenhydramine Hydrochloride) Xepa-Soul Pattinson and MAO inhibitors increase the anticholinergic activity of Benadryl DMP (Diphenhydramine Hydrochloride).

The antagonistic interaction observed with a joint appointment with psychostimulants.

Reduces the effectiveness of apomorphine as an emetic in the treatment of poisoning. Intensifies anticholinergic effects of drugs with anticholinergic activity.

Benadryl DMP Xepa-Soul Pattinson in case of emergency / overdose

Symptoms: dry mouth, difficulty breathing, persistent mydriasis, flushing, depression or excitement (more common in children), CNS confusion; children - the development of convulsions and death.

Treatment: induction of vomiting, gastric lavage, the prescription of activated charcoal, symptomatic and supportive therapy on a background of careful monitoring of respiration and blood pressure levels.

Phenylephrine Hydrochloride:

• Drug facts
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Product packaging
• Benadryl DMP (Phenylephrine Hydrochloride) reviews

Drug Facts

Active ingredients

(in each tablet)

Dexbrompheniramine Maleate 2 mg

Benadryl DMP (Phenylephrine Hydrochloride) Hydrochloride 10 mg

Purpose

Antihistamine

Nasal Decongestant

Uses

Temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies:

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product

• if you are now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
  

Ask a doctor before use if you have

• a breathing problem such as emphysema or chronic bronchitis
• glaucoma
• trouble urinating due to enlargement of the prostate gland
• heart disease
• high blood pressure
• thyroid disease
• diabetes
  

Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers.

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• avoid alcoholic drinks
• alcohol, sedatives, and tranquilizers may increase the drowsiness effect
• use caution when driving a motor vehicle or operating machinery
  

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• symptoms do not improve within 7 days or are accompanied by fever
  

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

Other information

Store at 15° - 30°C (59° - 86°F). Supplied in a tight, light-resistant container with a child-resistant cap. Benadryl DMP (Phenylephrine Hydrochloride) Tablets are dark purple, caplet-shaped, scored tablets, debossed "Poly" bisect "782" on one side and plain on the other.

Inactive ingredients

colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 aluminum lake, dibasic calcium phosphate dihydrate, FD &C Blue #1 aluminum lake, magnesium stearate, and silicified microcrystalline cellulose.

Questions? Comments?

Call1-800-882-1041

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355 Rev. 02/12

Product Packaging

The packaging below represents the labeling currently used.

Principal display panel and side panel for 60 tablets label:

NDC 50991-782-60

Benadryl DMP (Phenylephrine Hydrochloride)

Tablets

Antihistamine - Nasal Decongestant

Each tablet contains:

Dexbrompheniramine Maleate...2 mg

Benadryl DMP (Phenylephrine Hydrochloride) Hydrochloride...10 mg

60 Tablets

Usual

Dosage: See product foldout for full prescribing information.

Tamper evident by foil seal under cap. Do not use if foil seal is

broken or missing.

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN.

Store at controlled room temperature between 15°-30°C (59°-86°F).

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355

Rev. 02/12

Benadryl DMP (Phenylephrine Hydrochloride) Tablets Packaging Benadryl DMP (Phenylephrine Hydrochloride) Tablets Packaging

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
• Benadryl DMP (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

Benadryl DMP nitrite is indicated for sequential use with Benadryl DMP (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

Benadryl DMP (Sodium Citrate) Nitrite Injection is indicated for sequential use with Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP 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, Benadryl DMP (Sodium Citrate) Nitrite Injection and Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (Sodium Citrate) thiosulfate, simultaneously with Benadryl DMP (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 Benadryl DMP (Sodium Citrate) thiosulfate, with Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite and Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite, followed by Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite and Benadryl DMP (Sodium Citrate) thiosulfate.

Benadryl DMP (Sodium Citrate) nitrite injection and Benadryl DMP (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. Benadryl DMP (Sodium Citrate) nitrite should be administered first, followed immediately by Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite and Benadryl DMP (Sodium Citrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Benadryl DMP (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 Benadryl DMP 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 Benadryl DMP (Sodium Citrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Benadryl DMP (Sodium Citrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Benadryl DMP (Sodium Citrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (Sodium Citrate) thiosulfate and Benadryl DMP (Sodium Citrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Benadryl DMP (Sodium Citrate) Nitrite Injection consists of:

• One vial of Benadryl DMP (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: Benadryl DMP 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 Benadryl DMP (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. Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP nitrite.

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

5.3 Anemia

Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Benadryl DMP 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 Benadryl DMP (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 Benadryl DMP 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 Benadryl DMP (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Benadryl DMP (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, Benadryl DMP 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 Benadryl DMP (Sodium Citrate) nitrite is excreted in human milk. Because Benadryl DMP (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 Benadryl DMP (Sodium Citrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Benadryl DMP (Sodium Citrate) nitrite. In studies conducted with Long-Evans rats, Benadryl DMP (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 Benadryl DMP nitrite in conjunction with Benadryl DMP (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 Benadryl DMP (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.

Benadryl DMP (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 Benadryl DMP (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

Benadryl DMP (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

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

Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (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

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

Structure of Benadryl DMP (Sodium Citrate) Nitrite

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

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

Benadryl DMP (Sodium Citrate) Nitrite

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

Benadryl DMP (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. Benadryl DMP (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

Benadryl DMP (Sodium Citrate) Nitrite

When 4 mg/kg Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (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 Benadryl DMP (Sodium Citrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Benadryl DMP (Sodium Citrate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Benadryl DMP 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

Benadryl DMP (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

Benadryl DMP (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