Prescription Drug Information: LymePak (Page 2 of 4)

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 LYMEPAK in conjunction with penicillin.

7.3 Antacids and Iron Preparations

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

7.4 Oral Contraceptives

Concurrent use of tetracycline, including LYMEPAK, may render oral contraceptives less effective.

7.5 Isotretinoin

There have been reports of intracranial hypertension associated with the concomitant use of isotretinoin and doxycycline. Avoid the concomitant use of isotretinoin and LYMEPAK because isotretinoin is also known to cause pseudotumor cerebri (benign intracranial hypertension [see Warnings and Precautions (5.7)].

7.6 Barbiturates and Anti-Epileptics

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

7.7 Drug/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

LYMEPAK, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy [see Warnings and Precautions (5.1, 5.2), Data, Use in Specific Populations (8.4)]. 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.

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.

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 [see Warnings and Precautions (5.1, 5.2)].

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 there are other antibacterial drug options available to treat Lyme disease in lactating women and 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 LYMEPAK and for 5 days after the last dose.

8.4 Pediatric Use

The safety and efficacy of LYMEPAK has been established in pediatric patients 8 years of age and older, weighing 45 kg and greater.

Because of the effects of the tetracycline-class of drugs on tooth development and growth, use of LYMEPAK in pediatric patients younger than 8 years of age, weighing less than 45 kg is not recommended [see Warnings and Precautions (5.1, 5.2)].

8.5 Geriatric Use

Clinical studies of LYMEPAK did not report specific treatment outcomes of patients aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

The use of tetracyclines has been associated with hepatotoxicity.

8.7 Renal Impairment

Studies have shown no significant difference in the serum half-life of doxycycline [see Clinical Pharmacology (12.3)] . No dosage adjustment is warranted in patients with renal impairment.

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

LYMEPAK contains doxycycline hyclate, USP which is the hyclate salt form of doxycycline, a tetracycline class antibacterial drug derived from oxytetracycline.

The chemical name of 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 molecular formula for doxycycline hyclate is (C 22 H 24 N 2 O 8 ∙HCl) 2 ∙C 2 H 6 O∙H 2 O and the molecular weight is 1025.89. Doxycycline is a light-yellow crystalline powder. Doxycycline hyclate is soluble in water.

Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. The chemical structure of doxycycline hyclate is shown in Figure 1.

Figure 1: Structure of Doxycycline Hyclate

Figure 1
(click image for full-size original)

LYMEPAK tablets, for oral administration, contain 100 mg of doxycycline (equivalent to 115 mg doxycycline hyclate). Inert ingredients in the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, D&C yellow #10, FD&C blue #1, FD&C yellow #6, hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, stearic acid, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LYMEPAK is an antibacterial drug [see Microbiology (12.4)] .

12.3 Pharmacokinetics

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form.

Absorption

Doxycycline is virtually completely absorbed after oral administration. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours.

Elimination

Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall as low as 1–5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min.).

Specific Populations

Studies have shown no significant difference in serum half-life of doxycycline (range 18–22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter serum half-life.

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

Culture and susceptibility testing are not routinely performed to establish the diagnosis of early Lyme disease; standard methods for susceptibility testing of Borrelia burgdorferi have not been established. The in vitro susceptibility of Borrelia burgdorferi to doxycycline has been reported in the literature; however, the clinical significance of these findings is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results using in vitro mammalian cell assays have been reported for related antibacterial drugs (tetracycline, oxytetracycline).

Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

13.2 Animal Toxicology and/or Pharmacology

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO 4 , methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

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