Ditenate Suppositories

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
• Ditenate Suppositories (Doxylamine Succinate) reviews

1 INDICATIONS AND USAGE

Ditenate Suppositories (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

Ditenate Suppositories (Doxylamine Succinate) has not been studied in women with hyperemesis gravidarum.

Ditenate Suppositories (Doxylamine Succinate) is a fixed dose combination drug product of Ditenate Suppositories (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 Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate) tablets.

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

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

Ditenate Suppositories (Doxylamine Succinate) is contraindicated in women with any of the following conditions:

• Known hypersensitivity to Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate) .

• Known hypersensitivity to Ditenate Suppositories (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 Ditenate Suppositories 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

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

Ditenate Suppositories (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

Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate) with CNS depressants including alcohol

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

7.2 Drug-Food Interactions

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

8.1 Pregnancy

Pregnancy Category A

Ditenate Suppositories (Doxylamine Succinate) is intended for use in pregnant women.

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

Animal Data

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

Once daily treatment of pregnant rats with Ditenate Suppositories (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 Ditenate Suppositories (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 Ditenate Suppositories (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 Ditenate Suppositories.

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

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

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Ditenate Suppositories 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, Ditenate Suppositories (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

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

Ditenate Suppositories (Doxylamine Succinate) Succinate

Ditenate Suppositories (Doxylamine Succinate) succinate is classified as an antihistamine. The chemical name for Ditenate Suppositories (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:

Ditenate Suppositories (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 Ditenate Suppositories is unknown.

12.3 Pharmacokinetics

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

Ditenate Suppositories (Doxylamine Succinate) and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The C_max of Ditenate Suppositories (Doxylamine Succinate) and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.

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

Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate), N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

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

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

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

Inform women of the importance of not taking Ditenate Suppositories (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.

Ditenate Suppositories (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

Ditenate Suppositories (Doxylamine Succinate) (dye-CLEE-gis)

(doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets

What is Ditenate Suppositories (Doxylamine Succinate)?

- Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate) is safe and effective in children under 18 years of age.

Who should not take Ditenate Suppositories (Doxylamine Succinate)?

Do not take Ditenate Suppositories (Doxylamine Succinate) if you:

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

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

Before taking Ditenate Suppositories (Doxylamine Succinate), tell your healthcare provider about all of your medical conditions, including;

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

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

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

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

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

- If you take too much Ditenate Suppositories (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 Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate)?

Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate). Severe drowsiness can happen or become worse causing falls or accidents.

These are not all the possible side effects of Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate)?

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

- Keep Ditenate Suppositories (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 Ditenate Suppositories (Doxylamine Succinate) and all medicines out of the reach of children.

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

What are the ingredients in Ditenate Suppositories (Doxylamine Succinate)?

Active ingredient: Ditenate Suppositories (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

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• Ditenate Suppositories (Ephedrine Hydrochloride) reviews

Boxed Warning

FOR YOUR PROTECTION, DO NOT USE IF SEAL OVER MOUTH OF BOTTLE IS BROKEN OR MISSING. CAPUSLES ARE SEALED WITH A RED GELATIN BAND

Active ingredient

(in each capsule)

Ditenate Suppositories (Ephedrine Hydrochloride) Sulfate USP, 25 mg

Purpose

Bronchodilator

Indications

For temporary relief of shortness of breath, tightness of chest, and wheezing due to bronchial asthma. For the temporary relief of bronchial asthma. Eases breathing for asthma patients by reducing spasms of bronchial muscles.

Warnings

Do not use this product unless a diagnosis of asthma has been made by a doctor. Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor. Do not use this product if you have ever been hospitalized for asthma or if you are taking and prescription drug for asthma or if you are taking and prescription drug for asthma unless directed by a doctor.

Drug Interaction precaution

Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (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 of pharmacist before taking this product.

Ask a doctor before use if you have

heart disease

high blood pressure

thyroid disease

diabetes

trouble urinating due to an enlarged prostate gland

When using this product

Do not use more than directed. Nervousness, tremor, sleeplessness, nausea or loss of appetite may occur. Do not continue to use this product, but seek medical assistance immediately if symptoms are not relieved within 1 hour or become worse, consult your doctor.

Stop use and ask a doctor if

Symptoms are not relieved within 1 hour or become worse. Nervousness, tremor or sleeplessness become worse. Some users of this product may experience nervousness, tremor, sleeplessness, nausea, and loss of appetite. If these symptoms persist or become worse, consult your doctor.

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 20-25°C (68-77°F). Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. You may report side effects to FDA at 1-800-FDA-1088.

Inactive ingredients

Colloidal Silicon Dioxide, Corn Starch, Magnesium Stearate. Capsule shell contains: FD&C Red #3 and Gelatin.

Manufactured by

West-ward Pharmaceutical Corp.

Eatontown, N.J. 07724

Label

Front

Back

Theophylline:

• Description
• Clinical pharmacology
• Clinical studies
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Ditenate Suppositories (Theophylline) reviews

DESCRIPTION

Ditenate Suppositories (Theophylline)^® (theophylline, anhydrous) Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients.

Ditenate Suppositories (Theophylline) is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous Ditenate Suppositories (Theophylline) has the chemical name 1H-Purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous Ditenate Suppositories (Theophylline) is C₇H₈N₄O₂ with a molecular weight of 180.17.

Each controlled-release tablet for oral administration, contains 400 or 600 mg of anhydrous Ditenate Suppositories (Theophylline).

Inactive Ingredients: cetostearyl alcohol, hydroxyethyl cellulose, magnesium stearate, povidone and talc.

Ditenate Suppositories (Theophylline) 400 mg

CLINICAL PHARMACOLOGY

Mechanism of Action

Ditenate Suppositories has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of Ditenate Suppositories (Theophylline) are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with Ditenate Suppositories (Theophylline) appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Ditenate Suppositories (Theophylline) increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship

Bronchodilation occurs over the serum Ditenate Suppositories (Theophylline) concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum Ditenate Suppositories (Theophylline) concentrations >10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum Ditenate Suppositories (Theophylline) concentrations >20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum Ditenate Suppositories (Theophylline) concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics

Overview: Ditenate Suppositories is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Ditenate Suppositories (Theophylline) does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of Ditenate Suppositories (Theophylline) vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I ) and co-administration of other drugs (see Table II ) can significantly alter the pharmacokinetic characteristics of Ditenate Suppositories (Theophylline). Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Ditenate Suppositories (Theophylline) concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter Ditenate Suppositories (Theophylline) clearance (see PRECAUTIONS, Laboratory Tests ).

Note: In addition to the factors listed above, Ditenate Suppositories (Theophylline) clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Ditenate Suppositories (Theophylline).

Absorption

Ditenate Suppositories (Theophylline)^® administered in the fed state is completely absorbed after oral administration.

In a single-dose crossover study, two 400 mg Ditenate Suppositories (Theophylline) Tablets were administered to 19 normal volunteers in the morning or evening immediately following the same standardized meal (769 calories consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). There was no evidence of dose dumping nor were there any significant differences in pharmacokinetic parameters attributable to time of drug administration. On the morning arm, the pharmacokinetic parameters were AUC=241.9±83.0 mcg hr/mL, C_max=9.3±2.0 mcg/mL, T_max=12.8±4.2 hours. On the evening arm, the pharmacokinetic parameters were AUC=219.7±83.0 mcg hr/mL, C_max=9.2±2.0 mcg/mL, T_max=12.5±4.2 hours.

A study in which Ditenate Suppositories (Theophylline) 400 mg Tablets were administered to 17 fed adult asthmatics produced similar Ditenate Suppositories (Theophylline) level-time curves when administered in the morning or evening. Serum levels were generally higher in the evening regimen but there were no statistically significant differences between the two regimens.

A single-dose study in 15 normal fasting male volunteers whose Ditenate Suppositories (Theophylline) inherent mean elimination half-life was verified by a liquid Ditenate Suppositories (Theophylline) product to be 6.9±2.5 (SD) hours were administered two or three 400 mg Ditenate Suppositories (Theophylline)^® Tablets. The relative bioavailability of Ditenate Suppositories (Theophylline) given in the fasting state in comparison to an immediate-release product was 59%. Peak serum Ditenate Suppositories (Theophylline) levels occurred at 6.9±5.2 (SD) hours, with a normalized (to 800 mg) peak level being 6.2±2.1 (SD). The apparent elimination half-life for the 400 mg Ditenate Suppositories (Theophylline) Tablets was 17.2±5.8 (SD) hours.

Steady-state pharmacokinetics were determined in a study in 12 fasted patients with chronic reversible obstructive pulmonary disease. All were dosed with two 400 mg Ditenate Suppositories (Theophylline) Tablets given once daily in the morning and a reference controlled-release BID product administered as two 200 mg tablets given 12 hours apart. The pharmacokinetic parameters obtained for Ditenate Suppositories (Theophylline) Tablets given at doses of 800 mg once daily in the morning were virtually identical to the corresponding parameters for the reference drug when given as 400 mg BID. In particular, the AUC, C_max and C_min values obtained in this study were as follows:

Single-dose studies in which subjects were fasted for twelve (12) hours prior to and an additional four (4) hours following dosing, demonstrated reduced bioavailability as compared to dosing with food. One single-dose study in 20 normal volunteers dosed with two (2) 400 mg tablets in the morning, compared dosing under these fasting conditions with dosing immediately prior to a standardized breakfast (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat). Under fed conditions, the pharmacokinetic parameters were: AUC=231.7±92.4 mcg hr/mL, C_max=8.4±2.6 mcg/mL, T_max=17.3±6.7 hours. Under fasting conditions, these parameters were AUC=141.2±6.53 mcg hr/mL, C_max=5.5±1.5 mcg/mL, T_max=6.5±2.1 hours.

Another single-dose study in 21 normal male volunteers, dosed in the evening, compared fasting to a standardized high calorie, high fat meal (870-1,020 calories, consisting of 33 grams protein, 55-75 grams fat, 58 grams carbohydrates). In the fasting arm subjects received one Ditenate Suppositories (Theophylline)^® 400 mg Tablet at 8 p.m. after an eight hour fast followed by a further four hour fast. In the fed arm, subjects were again dosed with one 400 mg Ditenate Suppositories (Theophylline) Tablet, but at 8 p.m. immediately after the high fat content standardized meal cited above. The pharmacokinetic parameters (normalized to 800 mg) fed were AUC=221.8±40.9 mcg hr/mL, C_max=10.9±1.7 mcg/mL, T_max=11.8±2.2 hours. In the fasting arm, the pharmacokinetic parameters (normalized to 800 mg) were AUC=146.4±40.9 mcg hr/mL, C_max=6.7±1.7 mcg/mL, T_max=7.3±2.2 hours.

Thus, administration of single Ditenate Suppositories (Theophylline) doses to healthy normal volunteers, under prolonged fasted conditions (at least 10 hour overnight fast before dosing followed by an additional four (4) hour fast after dosing) results in decreased bioavailability. However, there was no failure of this delivery system leading to a sudden and unexpected release of a large quantity of Ditenate Suppositories (Theophylline) with Ditenate Suppositories (Theophylline) Tablets even when they are administered with a high fat, high calorie meal.

Similar studies were conducted with the 600 mg Ditenate Suppositories (Theophylline) Tablet. A single-dose study in 24 subjects with an established Ditenate Suppositories (Theophylline) clearance of ≤4 L/hr, compared the pharmacokinetic evaluation of one 600 mg Ditenate Suppositories (Theophylline) Tablet and one and one-half 400 mg Ditenate Suppositories (Theophylline) Tablets under fed (using a standard high fat diet) and fasted conditions. The results of this 4-way randomized crossover study demonstrate the bioequivalence of the 400 mg and 600 mg Ditenate Suppositories (Theophylline) Tablets. Under fed conditions, the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=214.64±55.88 mcg hr/mL, C_max=10.58±2.21 mcg/mL and T_max=9.00±2.64 hours, and for the 600 mg tablet were AUC=207.85±48.9 mcg hr/mL, C_max=10.39±1.91 mcg/mL and T_max=9.58±1.86 hours. Under fasted conditions the pharmacokinetic results for the one and one-half 400 mg tablets were AUC=191.85 ±51.1 mcg hr/mL, C_max= 7.37±1.83 mcg/mL and T_max=8.08±4.39 hours; and for the 600 mg tablet were AUC=199.39±70.27 mcg hr/mL, C_max=7.66±2.09 mcg/mL and T_max=9.67±4.89 hours.

In this study the mean fed/fasted ratios for the one and one-half 400 mg tablets and the 600 mg tablet were about 112% and 104%, respectively.

In another study, the bioavailability of the 600 mg Ditenate Suppositories (Theophylline) Tablet was examined with morning and evening administration. This single-dose, crossover study in 22 healthy males was conducted under fed (standard high fat diet) conditions. The results demonstrated no clinically significant difference in the bioavailability of the 600 mg Ditenate Suppositories (Theophylline) Tablet administered in the morning or in the evening. The results were: AUC=233.6±45.1 mcg hr/mL, C_max=10.6±1.3 mcg/mL and T_max=12.5±3.2 hours with morning dosing; AUC=209.8±46.2 mcg hr/mL, C_max=9.7±1.4 mcg/mL and T_max=13.7±3.3 hours with evening dosing. The PM/AM ratio was 89.3%.

The absorption characteristics of Ditenate Suppositories (Theophylline)^® Tablets (theophylline, anhydrous) have been extensively studied. A steady-state crossover bioavailability study in 22 normal males compared two Ditenate Suppositories (Theophylline) 400 mg Tablets administered q24h at 8 a.m. immediately after breakfast with a reference controlled-release Ditenate Suppositories (Theophylline) product administered BID in fed subjects at 8 a.m. immediately after breakfast and 8 p.m. immediately after dinner (769 calories, consisting of 97 grams carbohydrates, 33 grams protein and 27 grams fat).

The pharmacokinetic parameters for Ditenate Suppositories (Theophylline) 400 mg Tablets under these steady-state conditions were AUC=203.3±87.1 mcg hr/mL, C_max=12.1±3.8 mcg/mL, C_min=4.50±3.6, T_max=8.8±4.6 hours. For the reference BID product, the pharmacokinetic parameters were AUC=219.2±88.4 mcg hr/mL, C_max =11.0±4.1 mcg/mL, C_min=7.28±3.5, T_max=6.9±3.4 hours. The mean percent fluctuation [(C_max-C_min/C_min)x100]=169% for the once-daily regimen and 51% for the reference product BID regimen.

The bioavailability of the 600 mg Ditenate Suppositories (Theophylline) Tablet was further evaluated in a multiple dose, steady-state study in 26 healthy males comparing the 600 mg Tablet to one and one-half 400 mg Ditenate Suppositories (Theophylline) Tablets. All subjects had previously established Ditenate Suppositories (Theophylline) clearances of ≤4 L/hr and were dosed once-daily for 6 days under fed conditions. The results showed no clinically significant difference between the 600 mg and one and one-half 400 mg Ditenate Suppositories (Theophylline) Tablet regimens. Steady-state results were:

The bioavailability ratio for the 600/400 mg tablets was 98.8%. Thus, under all study conditions the 600 mg tablet is bioequivalent to one and one-half 400 mg tablets.

Studies demonstrate that as long as subjects were either consistently fed or consistently fasted, there is similar bioavailability with once-daily administration of Ditenate Suppositories (Theophylline) Tablets whether dosed in the morning or evening.

Distribution

Once Ditenate Suppositories enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound Ditenate Suppositories (Theophylline) distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of Ditenate Suppositories (Theophylline) is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Ditenate Suppositories (Theophylline) passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva Ditenate Suppositories (Theophylline) concentrations approximate unbound serum concentrations, but are not reliable for routine or therapeutic monitoring unless special techniques are used. An increase in the volume of distribution of Ditenate Suppositories (Theophylline), primarily due to reduction in plasma protein binding, occurs in premature neonates, patients with hepatic cirrhosis, uncorrected acidemia, the elderly and in women during the third trimester of pregnancy. In such cases, the patient may show signs of toxicity at total (bound+unbound) serum concentrations of Ditenate Suppositories (Theophylline) in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug. Similarly, a patient with decreased Ditenate Suppositories (Theophylline) binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum Ditenate Suppositories (Theophylline) concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum Ditenate Suppositories (Theophylline) concentration provides a more reliable means of dosage adjustment than measurement of total serum Ditenate Suppositories (Theophylline) concentration. Generally, concentrations of unbound Ditenate Suppositories (Theophylline) should be maintained in the range of 6-12 mcg/mL.

Metabolism

Following oral dosing, Ditenate Suppositories (Theophylline) does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Ditenate Suppositories (Theophylline) dose is N-methylated to caffeine. Ditenate Suppositories (Theophylline) demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Ditenate Suppositories (Theophylline) metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Ditenate Suppositories (Theophylline) and serum concentrations in adults with normal renal function are <1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Ditenate Suppositories (Theophylline) concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Ditenate Suppositories (Theophylline) concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Ditenate Suppositories (Theophylline) biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Ditenate Suppositories (Theophylline) metabolism, non-linearity of elimination may begin in some patients at serum Ditenate Suppositories (Theophylline) concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Ditenate Suppositories (Theophylline) concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Ditenate Suppositories (Theophylline) concentrations (see DOSAGE AND ADMINISTRATION, Table VI ). Accurate prediction of dose-dependency of Ditenate Suppositories (Theophylline) metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum Ditenate Suppositories (Theophylline) concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Ditenate Suppositories (Theophylline) concentration in response to dosage changes.

Excretion

In neonates, approximately 50% of the Ditenate Suppositories dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Ditenate Suppositories (Theophylline) dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Ditenate Suppositories (Theophylline) is excreted unchanged in the urine and since active metabolites of Ditenate Suppositories (Theophylline) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, the large fraction of the Ditenate Suppositories (Theophylline) dose excreted in the urine as unchanged Ditenate Suppositories (Theophylline) and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations in neonates with reduced renal function (See WARNINGS ).

Serum Concentrations at Steady-State

After multiple doses of Ditenate Suppositories (Theophylline), steady-state is reached in 30-65 hours (average 40 hours) in adults. At steady-state, on a dosage regimen with 24-hour intervals, the expected mean trough concentration is approximately 50% of the mean peak concentration, assuming a mean Ditenate Suppositories (Theophylline) half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid Ditenate Suppositories (Theophylline) clearance. In these patients administration of Ditenate Suppositories (Theophylline)^® may be required more frequently (every 12 hours).

Special Populations

Geriatric

The clearance of Ditenate Suppositories (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in elderly patients (see WARNINGS ).

Pediatrics

The clearance of Ditenate Suppositories is very low in neonates (see WARNINGS ). Ditenate Suppositories (Theophylline) clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged Ditenate Suppositories (Theophylline) in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).

Gender

Gender differences in Ditenate Suppositories (Theophylline) clearance are relatively small and unlikely to be of clinical significance. Significant reduction in Ditenate Suppositories (Theophylline) clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race

Pharmacokinetic differences in Ditenate Suppositories clearance due to race have not been studied.

Renal Insufficiency

Only a small fraction, e.g., about 10%, of the administered Ditenate Suppositories (Theophylline) dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little Ditenate Suppositories (Theophylline) is excreted unchanged in the urine and since active metabolites of Ditenate Suppositories (Theophylline) (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children >3 months of age. In contrast, approximately 50% of the administered Ditenate Suppositories (Theophylline) dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in neonates with decreased renal function (see WARNINGS ).

Hepatic Insufficiency

Ditenate Suppositories clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in patients with reduced hepatic function (see WARNINGS ).

Congestive Heart Failure (CHF)

Ditenate Suppositories (Theophylline) clearance is decreased by 50% or more in patients with CHF. The extent of reduction in Ditenate Suppositories (Theophylline) clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since Ditenate Suppositories (Theophylline) clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in patients with CHF (see WARNINGS ).

Smokers

Tobacco and marijuana smoking appears to increase the clearance of Ditenate Suppositories by induction of metabolic pathways. Ditenate Suppositories (Theophylline) clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase Ditenate Suppositories (Theophylline) clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in Ditenate Suppositories (Theophylline) clearance. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in patients who stop smoking (see WARNINGS ). Use of nicotine gum has been shown to have no effect on Ditenate Suppositories (Theophylline) clearance.

Fever

Fever, regardless of its underlying cause, can decrease the clearance of Ditenate Suppositories (Theophylline). The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of Ditenate Suppositories (Theophylline) clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum Ditenate Suppositories (Theophylline) concentrations. Children with rapid rates of Ditenate Suppositories (Theophylline) clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum Ditenate Suppositories (Theophylline) concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in patients with sustained fever (see WARNINGS ).

Miscellaneous

Other factors associated with decreased Ditenate Suppositories (Theophylline) clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in patients with any of these conditions (see WARNINGS ). Other factors associated with increased Ditenate Suppositories (Theophylline) clearance include hyperthyroidism and cystic fibrosis.

CLINICAL STUDIES

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that Ditenate Suppositories (Theophylline) decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-₂ agonists. Ditenate Suppositories (Theophylline) has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that Ditenate Suppositories (Theophylline) decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

INDICATIONS AND USAGE

Ditenate Suppositories (Theophylline) is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

CONTRAINDICATIONS

Ditenate Suppositories (Theophylline)^® is contraindicated in patients with a history of hypersensitivity to Ditenate Suppositories (Theophylline) or other components in the product.

WARNINGS

Concurrent Illness

Ditenate Suppositories should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Ditenate Suppositories (Theophylline) Clearance

There are several readily identifiable causes of reduced Ditenate Suppositories (Theophylline) clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Ditenate Suppositories (Theophylline) toxicity can occur . Careful consideration must be given to the benefits and risks of Ditenate Suppositories (Theophylline) use and the need for more intensive monitoring of serum Ditenate Suppositories (Theophylline) concentrations in patients with the following risk factors:

Age

• Neonates (term and premature)
• Children <1 year
• Elderly (>60 years)

Concurrent Diseases

• Acute pulmonary edema
• Congestive heart failure
• Cor-pulmonale
• Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods
• Hypothyroidism
• Liver disease; cirrhosis, acute hepatitis
• Reduced renal function in infants <3 months of age
• Sepsis with multi-organ failure
• Shock

Cessation of Smoking

Drug Interactions

Adding a drug that inhibits Ditenate Suppositories metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Ditenate Suppositories (Theophylline) metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II ).

When Signs or Symptoms of Ditenate Suppositories (Theophylline) Toxicity Are Present

Whenever a patient receiving Ditenate Suppositories (Theophylline) develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Ditenate Suppositories (Theophylline) toxicity (even if another cause may be suspected), additional doses of Ditenate Suppositories (Theophylline) should be withheld and a serum Ditenate Suppositories (Theophylline) concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI ).

Dosage Increases

Increases in the dose of Ditenate Suppositories (Theophylline) should not be made in response to an acute exacerbation of symptoms of chronic lung disease since Ditenate Suppositories (Theophylline) provides little added benefit to inhaled beta₂-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum Ditenate Suppositories (Theophylline) concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the Ditenate Suppositories (Theophylline) dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ).

As the rate of Ditenate Suppositories (Theophylline) clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum Ditenate Suppositories (Theophylline) concentration (see DOSAGE AND ADMINISTRATION, Table VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter Ditenate Suppositories clearance and require dosage adjustment should occur prior to initiation of Ditenate Suppositories (Theophylline) therapy, prior to increases in Ditenate Suppositories (Theophylline) dose, and during follow up (see WARNINGS ). The dose of Ditenate Suppositories (Theophylline) selected for initiation of therapy should be low and, if tolerated , increased slowly over a period of a week or longer with the final dose guided by monitoring serum Ditenate Suppositories (Theophylline) concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION , Table V).

Monitoring Serum Ditenate Suppositories (Theophylline) Concentrations

Serum Ditenate Suppositories (Theophylline) concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Ditenate Suppositories (Theophylline) concentration should be measured as follows:

• When initiating therapy to guide final dosage adjustment after titration.
• Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
• Whenever signs or symptoms of Ditenate Suppositories (Theophylline) toxicity are present.
• Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter Ditenate Suppositories (Theophylline) clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum Ditenate Suppositories (Theophylline) concentration; 12 hours after an evening dose or 9 hours after a morning dose at steady-state. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum Ditenate Suppositories (Theophylline) concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than 12 hours after the evening dose, or more than 9 hours after a morning dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of Ditenate Suppositories (Theophylline) toxicity are present, a serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the healthcare professional without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound Ditenate Suppositories (Theophylline) should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Ditenate Suppositories (Theophylline) cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests

As a result of its pharmacological effects, Ditenate Suppositories at serum concentrations within the 10-20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L, total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Ditenate Suppositories (Theophylline) at serum concentrations within the 10-20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dL after 4 weeks of Ditenate Suppositories (Theophylline)). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Ditenate Suppositories (Theophylline) in individual patients.

Information for Patients

The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with Ditenate Suppositories (Theophylline), even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that Ditenate Suppositories (Theophylline) interacts with a wide variety of drugs. The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as Ditenate Suppositories (Theophylline), since it may result in decreased Ditenate Suppositories (Theophylline) levels. If patients are already taking St. John’s Wort and Ditenate Suppositories (Theophylline) together, they should consult their healthcare professional before stopping the St. John’s Wort, since their Ditenate Suppositories (Theophylline) concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking Ditenate Suppositories (Theophylline), especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Ditenate Suppositories (Theophylline)^® Tablets can be taken once a day in the morning or evening. It is recommended that Ditenate Suppositories (Theophylline) be taken with meals. Patients should be advised that if they choose to take Ditenate Suppositories (Theophylline) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Ditenate Suppositories (Theophylline) Tablets are not to be chewed or crushed because it may lead to a rapid release of Ditenate Suppositories (Theophylline) with the potential for toxicity. The scored tablet may be split. Patients receiving Ditenate Suppositories (Theophylline) Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Ditenate Suppositories (Theophylline).

Drug Interactions

Ditenate Suppositories interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to Ditenate Suppositories (Theophylline) or another drug or occurrence of adverse effects without a change in serum Ditenate Suppositories (Theophylline) concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of Ditenate Suppositories (Theophylline) clearance is altered by another drug resulting in increased or decreased serum Ditenate Suppositories (Theophylline) concentrations. Ditenate Suppositories (Theophylline) only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with Ditenate Suppositories (Theophylline). The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state Ditenate Suppositories (Theophylline) regimen. If Ditenate Suppositories (Theophylline) is being initiated in a patient who is already taking a drug that inhibits Ditenate Suppositories (Theophylline) clearance (e.g., cimetidine, erythromycin), the dose of Ditenate Suppositories (Theophylline) required to achieve a therapeutic serum Ditenate Suppositories (Theophylline) concentration will be smaller. Conversely, if Ditenate Suppositories (Theophylline) is being initiated in a patient who is already taking a drug that enhances Ditenate Suppositories (Theophylline) clearance (e.g., rifampin), the dose of Ditenate Suppositories (Theophylline) required to achieve a therapeutic serum Ditenate Suppositories (Theophylline) concentration will be larger. Discontinuation of a concomitant drug that increases Ditenate Suppositories (Theophylline) clearance will result in accumulation of Ditenate Suppositories (Theophylline) to potentially toxic levels, unless the Ditenate Suppositories (Theophylline) dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits Ditenate Suppositories (Theophylline) clearance will result in decreased serum Ditenate Suppositories (Theophylline) concentrations, unless the Ditenate Suppositories (Theophylline) dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with Ditenate Suppositories (Theophylline) or do not produce a clinically significant interaction (i.e., <15% change in Ditenate Suppositories (Theophylline) clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995. New interactions are continuously being reported for Ditenate Suppositories (Theophylline), especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with Ditenate Suppositories (Theophylline) if it is not listed in Table II. Before addition of a newly available drug in a patient receiving Ditenate Suppositories (Theophylline), the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and Ditenate Suppositories (Theophylline) has been reported.

Drug-Food Interactions

The bioavailability of Ditenate Suppositories (Theophylline)^® Tablets (theophylline, anhydrous) has been studied with co-administration of food. In three single-dose studies, subjects given Ditenate Suppositories (Theophylline) 400 mg or 600 mg Tablets with a standardized high-fat meal were compared to fasted conditions. Under fed conditions, the peak plasma concentration and bioavailability were increased; however, a precipitous increase in the rate and extent of absorption was not evident (see Pharmacokinetics , Absorption). The increased peak and extent of absorption under fed conditions suggests that dosing should be ideally administered consistently either with or without food.

The Effect of Other Drugs on Ditenate Suppositories Serum Concentration Measurements

Most serum Ditenate Suppositories (Theophylline) assays in clinical use are immunoassays which are specific for Ditenate Suppositories (Theophylline). Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum Ditenate Suppositories (Theophylline) concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long term carcinogenicity studies have been carried out in mice and rats (oral doses 5-75 mg/kg). Results are pending.

Ditenate Suppositories (Theophylline) has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, Ditenate Suppositories (Theophylline), administered to mating pairs of B6C3F₁ mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0-3.0 times the human dose on a mg/m² basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, Ditenate Suppositories (Theophylline) was administered to F344 rats and B6C3F₁ mice at oral doses of 40-300 mg/kg (approximately 2.0 times the human dose on a mg/m² basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy: Teratogenic Effects: Category C

In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, Ditenate Suppositories (Theophylline) produced teratogenic effects.

In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m² basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis.

In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m² basis).

In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m² basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m² basis) increased the incidence of skeletal variations.

There are no adequate and well-controlled studies in pregnant women. Ditenate Suppositories (Theophylline) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Ditenate Suppositories is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Ditenate Suppositories (Theophylline) in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of Ditenate Suppositories (Theophylline) per day is likely to receive 10-20 mg of Ditenate Suppositories (Theophylline) per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Ditenate Suppositories (Theophylline) concentrations.

Pediatric Use

Ditenate Suppositories (Theophylline) is safe and effective for the approved indications in pediatric patients. The maintenance dose of Ditenate Suppositories (Theophylline) must be selected with caution in pediatric patients since the rate of Ditenate Suppositories (Theophylline) clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V ).

Geriatric Use

Elderly patients are at a significantly greater risk of experiencing serious toxicity from Ditenate Suppositories (Theophylline) than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of Ditenate Suppositories (Theophylline) is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Ditenate Suppositories (Theophylline) clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum Ditenate Suppositories (Theophylline) concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Ditenate Suppositories (Theophylline) after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum Ditenate Suppositories (Theophylline) concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Ditenate Suppositories (Theophylline) Concentrations, and DOSAGE AND ADMINISTRATION ). The maximum daily dose of Ditenate Suppositories (Theophylline) in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum Ditenate Suppositories (Theophylline) concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Ditenate Suppositories (Theophylline) doses greater than 400 mg/d should be prescribed with caution in elderly patients. Ditenate Suppositories (Theophylline) should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

ADVERSE REACTIONS

Adverse reactions associated with Ditenate Suppositories (Theophylline) are generally mild when peak serum Ditenate Suppositories (Theophylline) concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum Ditenate Suppositories (Theophylline) concentrations exceed 20 mcg/mL, however, Ditenate Suppositories (Theophylline) produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when Ditenate Suppositories (Theophylline) therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age). During the initiation of Ditenate Suppositories (Theophylline) therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of Ditenate Suppositories (Theophylline) therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ). In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum Ditenate Suppositories (Theophylline) concentrations within the therapeutic range (i.e., 10-20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued Ditenate Suppositories (Theophylline) therapy and the potential therapeutic benefit of alternative treatment.

Other adverse reactions that have been reported at serum Ditenate Suppositories (Theophylline) concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactoid reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum Ditenate Suppositories (Theophylline) concentrations ≥15 mcg/mL. There have been a few isolated reports of seizures at serum Ditenate Suppositories (Theophylline) concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Ditenate Suppositories (Theophylline) concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Ditenate Suppositories (Theophylline) concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Ditenate Suppositories (Theophylline) concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum Ditenate Suppositories (Theophylline) concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).

OVERDOSAGE

General

The chronicity and pattern of Ditenate Suppositories overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient’s rate of Ditenate Suppositories (Theophylline) clearance. The most common causes of chronic Ditenate Suppositories (Theophylline) overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Ditenate Suppositories (Theophylline) clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Ditenate Suppositories (Theophylline) concentration to determine whether a dose increase is safe.

Severe toxicity from Ditenate Suppositories (Theophylline) overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of Ditenate Suppositories (Theophylline) was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum Ditenate Suppositories (Theophylline) concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum Ditenate Suppositories (Theophylline) concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum Ditenate Suppositories (Theophylline) concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from Ditenate Suppositories (Theophylline) is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of Ditenate Suppositories (Theophylline) overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum Ditenate Suppositories (Theophylline) concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Ditenate Suppositories (Theophylline) concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum Ditenate Suppositories (Theophylline) concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum Ditenate Suppositories (Theophylline) concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of Ditenate Suppositories (Theophylline) overdose according to the mode of overdose are listed in Table IV.

Other manifestations of Ditenate Suppositories (Theophylline) toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum Ditenate Suppositories (Theophylline) concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from Ditenate Suppositories (Theophylline) toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management

General Recommendations for Patients with Symptoms of Ditenate Suppositories (Theophylline) Overdose or Serum Ditenate Suppositories (Theophylline) Concentrations >30 mcg/mL (Note: Serum Ditenate Suppositories (Theophylline) concentrations may continue to increase after presentation of the patient for medical care.)

• While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
• Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
• Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of Ditenate Suppositories (Theophylline) overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with Ditenate Suppositories (Theophylline) overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Ditenate Suppositories (Theophylline). Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
• Anticipate Need for Anticonvulsants In patients with Ditenate Suppositories (Theophylline) overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum Ditenate Suppositories (Theophylline) concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum Ditenate Suppositories (Theophylline) concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of Ditenate Suppositories (Theophylline) (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance Ditenate Suppositories (Theophylline) clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of Ditenate Suppositories (Theophylline) required to induce seizures (i.e., markedly increases the LD₅₀). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance Ditenate Suppositories (Theophylline) clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
• Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum Ditenate Suppositories (Theophylline) concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
• Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of Ditenate Suppositories (Theophylline) throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of Ditenate Suppositories (Theophylline) bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in Ditenate Suppositories (Theophylline) overdoses. Although ipecac induces emesis, it does not reduce the absorption of Ditenate Suppositories (Theophylline) unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
• Serum Ditenate Suppositories (Theophylline) Concentration Monitoring The serum Ditenate Suppositories (Theophylline) concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum Ditenate Suppositories (Theophylline) concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Ditenate Suppositories (Theophylline) from the gastrointestinal tract. Serial monitoring of serum Ditenate Suppositories (Theophylline) serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
• General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum Ditenate Suppositories (Theophylline) level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
• Enhance clearance of Ditenate Suppositories (Theophylline) Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of Ditenate Suppositories (Theophylline) at least twofold by adsorption of Ditenate Suppositories (Theophylline) secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed Ditenate Suppositories (Theophylline) from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Ditenate Suppositories (Theophylline) and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of Ditenate Suppositories (Theophylline) removal should be instituted (see OVERDOSAGE, Extracorporeal Removal ).

Specific Recommendations

Acute Overdose

• Serum Concentration >20<30 mcg/mL
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Ditenate Suppositories concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30<100 mcg/mL
  • Administer multiple dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Ditenate Suppositories (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration>100 mcg/mL
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
  • Monitor the patient and obtain serial Ditenate Suppositories (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

• Serum Concentration >20<30 mcg/mL (with manifestations of Ditenate Suppositories (Theophylline) toxicity)
  • Administer a single dose of oral activated charcoal.
  • Monitor the patient and obtain a serum Ditenate Suppositories (Theophylline) concentration in 2-4 hours to insure that the concentration is not increasing.
• Serum Concentration >30 mcg/mL in patients <60 years of age
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Monitor the patient and obtain serial Ditenate Suppositories (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
  • Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
• Serum Concentration >30 mcg/mL in patients ≥ 60 years of age
  • Consider prophylactic anticonvulsant therapy.
  • Administer multiple-dose oral activated charcoal and measures to control emesis.
  • Consider extracorporeal removal even if the patient has not experienced a seizure.
  • Monitor the patient and obtain serial Ditenate Suppositories (Theophylline) concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of Ditenate Suppositories (Theophylline) clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing Ditenate Suppositories (Theophylline) clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum Ditenate Suppositories (Theophylline) concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Ditenate Suppositories (Theophylline) from the tissue compartment. Peritoneal dialysis is ineffective for Ditenate Suppositories (Theophylline) removal; exchange transfusions in neonates have been minimally effective.

DOSAGE AND ADMINISTRATION

Ditenate Suppositories ^® 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Ditenate Suppositories (Theophylline) be taken with meals. Patients should be advised that if they choose to take Ditenate Suppositories (Theophylline) with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food.

Ditenate Suppositories (Theophylline)^® Tablets are not to be chewed or crushed because it may lead to a rapid release of Ditenate Suppositories (Theophylline) with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Ditenate Suppositories (Theophylline) 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual Ditenate Suppositories (Theophylline).

Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release Ditenate Suppositories (Theophylline) product may be transferred to once-daily administration of 400 mg or 600 mg Ditenate Suppositories (Theophylline) Tablets on a mg-for-mg basis.

It must be recognized that the peak and trough serum Ditenate Suppositories (Theophylline) levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen.

General Considerations

The steady-state peak serum Ditenate Suppositories (Theophylline) concentration is a function of the dose, the dosing interval, and the rate of Ditenate Suppositories (Theophylline) absorption and clearance in the individual patient. Because of marked individual differences in the rate of Ditenate Suppositories (Theophylline) clearance, the dose required to achieve a peak serum Ditenate Suppositories (Theophylline) concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Ditenate Suppositories (Theophylline) clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single Ditenate Suppositories (Theophylline) dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Ditenate Suppositories (Theophylline) dose required to achieve a therapeutic serum Ditenate Suppositories (Theophylline) concentration in a given population may result in either sub-therapeutic or potentially toxic serum Ditenate Suppositories (Theophylline) concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum Ditenate Suppositories (Theophylline) concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of Ditenate Suppositories (Theophylline) must be individualized on the basis of peak serum Ditenate Suppositories (Theophylline) concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum Ditenate Suppositories (Theophylline) concentrations to reach the new steady-state. Dosage adjustment should be guided by serum Ditenate Suppositories (Theophylline) concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ).

If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum Ditenate Suppositories (Theophylline) concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum Ditenate Suppositories (Theophylline) concentrations should be monitored at frequent intervals, e.g., every 24 hours.

Ditenate Suppositories (Theophylline) distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight.

Table V contains Ditenate Suppositories (Theophylline) dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for Ditenate Suppositories (Theophylline) dosage adjustment based upon serum Ditenate Suppositories (Theophylline) concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Ditenate Suppositories (Theophylline) concentration.

Table V. Dosing initiation and titration (as anhydrous Ditenate Suppositories (Theophylline)). *

• A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance.

• B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Ditenate Suppositories (Theophylline) Concentrations:
  
  • In children 12-15 years of age, the Ditenate Suppositories (Theophylline) dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced Ditenate Suppositories (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Ditenate Suppositories (Theophylline) concentrations.
    

  • In adolescents ≥16 years and adults, including the elderly, the Ditenate Suppositories (Theophylline) dose should not exceed 400 mg/day in the presence of risk factors for reduced Ditenate Suppositories (Theophylline) clearance (see WARNINGS ) or if it is not feasible to monitor serum Ditenate Suppositories (Theophylline) concentrations.

*Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.

HOW SUPPLIED

Ditenate Suppositories (Theophylline)^® (theophylline, anhydrous) Controlled-Release Tablets 400 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-251-01) or 500 tablets (NDC 67781-251-05). Each round, white 400 mg tablet bears the symbol PF on the scored side and U400 on the other side.

Ditenate Suppositories (Theophylline)^® (theophylline, anhydrous) Controlled-Release Tablets 600 mg are supplied in white, opaque plastic, child-resistant bottles containing 100 tablets (NDC 67781-252-01). Each rectangular, concave, white 600 mg tablet bears the symbol PF on the scored side and U 600 on the other side.

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container.

©2011, Purdue Pharmaceutical Products L.P.

Dist. by: Purdue Pharmaceutical Products L.P.

Stamford, CT 06901-3431

Revised 10/2011

300945-0B

Ditenate Suppositories (Theophylline) Tablets

400 mg Tablets

NDC 677781-251-01

Ditenate Suppositories (Theophylline) Tablets 400 mg Tablets NDC 677781-251-01

Ditenate Suppositories (Theophylline) Tablets

600 mg Tablets

NDC 677781-252-01

Ditenate Suppositories (Theophylline) Tablets 600 mg Tablets NDC 677781-252-01