Doxycycline Hyclate: Package Insert and Label Information (Page 2 of 3)

6 ADVERSE REACTIONS

The following adverse reactions have been identified during clinical trials or post-approval use of tetracycline-class drugs, including doxycycline. 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.

Gastrointestinal

Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development [See Warnings and Precautions (5.1)]. Instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration (2.1)].

Skin

Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity has been reported [see Warnings and Precautions (5.3)]

Renal

Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.7)].

Hypersensitivity reactions

Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systematic lupus erythematosus and drug reaction with eosinophilia and systematic symptoms (DRESS).

Blood

Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Intracranial Hypertension

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines [see Warnings and Precautions (5.6)].

Thyroid Gland Changes

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

7 DRUG INTERACTIONS

7.1 Anticoagulant Drugs

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

7.2 Penicillin

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines, including doxycycline hyclate in conjunction with penicillin.

7.3 Antacids and Iron Preparations

Absorption of tetracyclines, including doxycycline hyclate is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations.

7.4 Oral Contraceptives

Concurrent use of tetracyclines, including doxycycline hyclate may render oral contraceptives less effective.

7.5 Barbiturates and Anti-Epileptics

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

7.6 Penthrane^®

The concurrent use of tetracycline and Penthrane^® (methoxyflurane) has been reported to result in fatal renal toxicity.

7.7 Drug and Laboratory Test Interactions

False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Doxycycline hyclate, like other tetracycline-class antibacterial drugs, may cause discoloration deciduous teeth, and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy [see Warnings and Precautions (5.1) and (5.2)]. Available data from published studies over decades have not shown a difference in major birth defect risk compared to unexposed pregnancies with doxycycline exposure in the first trimester of pregnancy (see Data). There are no available data on the risk of miscarriage following exposure to doxycycline in pregnancy. Advise the patient of the potential risk to the fetus if doxycycline hyclate is used during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data:

A retrospective cohort study of 1,690 pregnant patients who received doxycycline prescriptions in the first trimester of pregnancy compared to an unexposed pregnant cohort showed no difference in the major malformation rate. There is no information on the dose or duration of treatment, or if the patients actually ingested the doxycycline that was prescribed.

Other published studies on exposure to doxycycline in the first trimester of pregnancy have small sample sizes; however, these studies have not shown an increased risk of major malformations.

The use of tetracyclines during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. [see Warnings and Precautions (5.1,5.2)].

Animal Data:

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy

8.2 Lactation

Risk Summary

Based on available published data, doxycycline is present in human milk. There are no data that inform the levels of doxycycline in breastmilk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with doxycycline hyclate and for 5 days after the last dose.

8.3 Females and Males of Reproductive Potential

Infertility

Based on findings from a fertility study in animals, doxycycline may impair female and male fertility. The reversibility of this finding is unclear. [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline hyclate in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies [see Warnings and Precautions (5.1, 1.1) and Dosage and Administration (2.1, 2.5)].

8.5 Geriatric Use

Clinical studies of doxycycline hyclate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Doxycycline Hyclate Tablets each contains less than 1 mg of sodium.

10 OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

11 DESCRIPTION

Doxycycline Hyclate Tablets USP contain doxycycline hyclate, a tetracycline class drug synthetically derived from oxytetracycline, in an immediate release formulation for oral administration.

The molecular formula of doxycycline hyclate is (C₂₂ H₂₄ N₂ O₈ ●HCl)₂ ●C₂ H₆ O●H₂ O and the molecular weight of doxycycline hyclate is 1025.87. The chemical name for doxycycline hyclate is: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.

The structural formula for doxycycline hyclate is:

Figure 1: Structure of Doxycycline Hyclate

Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates.

Doxycycline Hyclate Tablets USP:

Doxycycline hyclate tablets USP are available as 75 mg and 150 mg tablets. Each 75 mg tablet contains 86.6 mg of doxycycline hyclate equivalent to 75 mg of doxycycline. Each 150 mg tablet contains 173.2 mg of doxycycline hyclate equivalent to 150 mg of doxycycline.

Inactive ingredients in the tablet formulation are: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. Film-coating contains: FD & C Blue # 1 / Brilliant Blue FCF Aluminum Lake (75 mg Tablet), FD & C Yellow # 6 /Sunset Yellow FCF Aluminum Lake (75 mg Tablet), FD & C Blue #2 / Indigo Carmine AL (150 mg Tablet), iron oxide yellow (150 mg Tablet), polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide. Doxycycline hyclate tablets USP, 75 mg contain 0.34 mg (0.0146 mEq) of sodium. Doxycycline hyclate tablets USP, 150 mg contain 0.68 mg (0.0295 mEq) of sodium.

Doxycycline hyclate tablets USP meets USP Dissolution Test 3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Doxycycline is a tetracycline-class antimicrobial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

Doxycycline hyclate tablets: Following administration of a single 300 mg dose to adult volunteers, average peak plasma doxycycline levels were 3.0 mcg per mL at 3 hours, decreasing to 1.18 mcg per mL at 24 hours. The mean C_max and AUC_0-∞ of doxycycline are 24% and 15% lower, respectively, following single dose administration of doxycycline hyclate tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown.

Doxycycline hyclate capsules. Following administration of a single 300 mg dose to adult volunteers, average peak plasma doxycycline levels were 2.8 mcg per mL at 3 hours, decreasing to 1.1 mcg per mL at 24 hours. The mean C_max of doxycycline is approximately 20% lower and the AUC_0-∞ is unchanged following single dose administration of doxycycline hyclate capsules with a high fat meal (including milk) compared to fasted conditions. The clinical significance of this decrease in C_max is unknown.

Excretion

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form.

Excretion of doxycycline by the kidney is about 40% per 72 hours in individuals with a creatinine clearance of about 75 mL per minute. This percentage may fall as low as 1% per 72 hours to 5% per 72 hours in individuals with a creatinine clearance below 10 mL per minute. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.

Pediatric Patients

Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 children (2-18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27-10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11-8.12] L/h/70 kg, N=33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0.041-0.202] L/kg/h, N=10) did not differ significantly from those >8 to 18 years of age (0.081 [0.035-0.126] L/kg/h, N=8). In pediatric patients weighing >45 kg no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.050 L/kg/h, N=1) and those >8 years of age (0.044 [0.014-0.121] L/kg/h, N=25). No clinically significant difference in CL differences between oral and IV were observed in the small cohort of pediatric patients who received the oral (N=19) or IV (N=21) formulation alone.

12.4 Microbiology

Mechanism of Action

Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.

Resistance

Cross resistance with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-negative bacteria:

Acinetobacter species

Bartonella bacilliformis

Brucella species

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-positive bacteria:

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae

Anaerobic bacteria :

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other bacteria:

Nocardiae and other aerobic Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae species

Treponema pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Parasites:

Balantidium coli

Entamoeba species

Plasmodium falciparum*

*Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum , but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline hyclate have not been conducted.

However, a 2 year carcinogenicity study with doxycycline administered daily by oral gavage to adult rats (20, 75, 200 mg/kg/day) demonstrated an increase in uterine polyps in female rats at 200 mg/kg/day (10 times the maximum recommended daily adult dose of doxycycline hyclate based on body surface area comparison) with no change in tumor incidence in male rats at the same dose. A 2-year carcinogenicity study with doxycycline administered daily by oral gavage to adult male (maximum dose 150 mg/kg/day) and female (maximum dose 300 mg/kg/day) mice showed no changes in tumor incidence, at approximately 4 and 7 times the maximum recommended daily adult dose of doxycycline hyclate, based on a body surface area comparison, respectively.

Mutagenesis and fertility studies have not been conducted with doxycycline hyclate. Mutagenesis studies with doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells or in an in vivo micronucleus assay in CD-1 mice. However, data from an in vitro mammalian chromosomal aberration assay conducted in CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline to Sprague-Dawley rats showed adverse effects on fertility and reproduction including increased time for mating, reduced sperm motility, velocity and concentration as well as increased pre and post implantation loss. Reduced sperm velocity was seen at the lowest dosage tested, 50 mg/kg/day which is 2.5 times the maximum recommended daily adult dose of doxycycline hyclate. Although doxycycline impairs the fertility of rats when administered at sufficient dosages, the effect of doxycycline hyclate on human fertility is unknown.