LymePak

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Tooth Discoloration and Enamel Hypoplasia [see Warnings and Precautions (5.1) ] Inhibition of Bone Growth [see Warnings and Precautions (5.2) ] Clostridium Difficile Associated Diarrhea [see Warnings and Precautions (5.3) ] Photosensitivity [see Warnings and Precautions (5.4) ] Severe Skin Reactions [see Warnings and Precautions (5.5) ] Jarisch-Herxheimer reaction [see Warnings and Precautions (5.6) ] Intracranial Hypertension [see Warnings and Precautions (5.7) ] The following adverse reactions have been observed during clinical trials or post-approval use of tetracycline-class drugs, including LYMEPAK. 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, and 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) ] . 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 (2.2) ] . Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erytherma multiforme, maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above [see Warnings and Precautions (5.4) ] . Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.8) ] . Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus and drug reaction with eosinophilia and systemic symptoms (DRESS). Jarisch-Herxheimer reaction has been reported in patients treated with doxycycline for early Lyme disease [see Warnings and Precautions (5.6) ] . Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) in adults and bulging fontanels in infants has been associated with the use of tetracycline [see Warnings and Precautions (5.7) ] . 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. Adverse reactions observed in patients receiving tetracycline class drugs including LYMEPAK were: anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS LYMEPAK is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. LYMEPAK is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. ( 4 )

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 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. Figure 1

2 DOSAGE AND ADMINISTRATION Adults and Pediatric Patients 8 years of age and older weighing 45 kg and above: 100 mg every 12 hours, for 21 days ( 2.1 ). 2.1 Dosage Adults and Pediatric Patients 8 years of age and older weighing 45 kg and above Administer LYMEPAK (100 mg) tablet every 12 hours for 21 days. 2.2 Important Administration Instructions The usual dosage and frequency of administration of LYMEPAK differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of adverse reactions. Administration of adequate amounts of fluid along with the tablets is recommended to wash down the tablet to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6) ]. If gastric irritation occurs, LYMEPAK may be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.

1 INDICATIONS AND USAGE LYMEPAK is a tetracycline class drug indicated for the treatment of early Lyme disease (as evidenced by erythema migrans) due to Borrelia burgdorferi in adults and pediatric patients 8 years of age and older weighing 45 kg and above. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of LYMEPAK and other antibacterial drugs, LYMEPAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.2 ). 1.1 Early Lyme Disease LYMEPAK is indicated for the treatment of early Lyme disease (as evidenced by erythema migrans) due to Borrelia burgdorferi in adults and pediatric patients 8 years of age and older weighing 45 kg and above. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of LYMEPAK and other antibacterial drugs, LYMEPAK should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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.

7 DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage ( 7.1 ) Avoid co-administration of LYMEPAK with penicillin ( 7.2 ) Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations ( 7.3 ) Concurrent use of tetracyclines, including LYMEPAK may render oral contraceptive less effective ( 7.4 ) Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline ( 7.6 ) 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.

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.

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.

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3 DOSAGE FORMS AND STRENGTHS LYMEPAK tablets are green, round, film-coated tablets engraved with LP-1 on one side. Each tablet contains 100 mg of doxycycline (equivalent to 115 mg doxycycline hyclate). Tablets containing 100 mg of doxycycline as doxycycline hyclate ( 3 )

LymePak Doxycycline Hyclate ANHYDROUS LACTOSE SILICON DIOXIDE D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C YELLOW NO. 6 HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE METHYLCELLULOSE (400 MPA.S) MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED SODIUM STARCH GLYCOLATE TYPE A POTATO STEARIC ACID TITANIUM DIOXIDE DOXYCYCLINE HYCLATE DOXYCYCLINE ANHYDROUS LP1

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.

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 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.

NDA209844

LymePak

Doxycycline Hyclate

62135-596

HUMAN PRESCRIPTION DRUG

ORAL

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.

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Blister Pack NDC 62135-596-86 LYMEPAK ™ (doxycycline hyclate tablets) 14 Tablets | 7 Day Supply 100mg* R x Only PRINCIPAL DISPLAY PANEL - 100 mg Tablet Blister Pack

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Administration and Safety Information for Patients and Caregivers Advise all patients taking LYMEPAK: to avoid excessive sunlight or artificial ultraviolet light while receiving LYMEPAK and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.4) ] . to drink fluids liberally along with LYMEPAK to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6) ] . that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of LYMEPAK is not markedly influenced by simultaneous ingestion of food or milk [see Dosage and Administration (2.2) ] . that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3) ] . that the use of LYMEPAK might increase the incidence of vaginal candidiasis [see Warnings and Precautions (5.10) ] . that LYMEPAK can make birth control pills less effective [see Drug Interactions (7.3) ] . Tooth Discoloration and Inhibition of Bone Growth Advise patients that LYMEPAK, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. Tell your healthcare provider right away if you become pregnant during treatment [see Warnings and Precautions (5.1 , 5.2 ) and Use in Specific Populations (8.1 , 8.4) ]. Lactation Advise women not to breastfeed during treatment with LYMEPAK and for 5 days after the last dose [see Use in Specific Populations (8.2) ]. Jarisch-Herxheimer Reaction Inform patients that a systemic reaction known as the Jarisch–Herxheimer reaction (JHR) may occur within 24 hours of starting LYMEPAK. Symptoms include shaking chills, fever, and intensification of skin rash and usually resolve within several hours. Advise patients to contact their health care provider if symptoms occur [see Warnings and Precautions 5.6 ] . Development of Resistance Patients should be counseled that antibacterial drugs, including LYMEPAK should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When LYMEPAK is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by LYMEPAK or other antibacterial drugs in the future [see Warnings and Precautions 5.9 ] . Diarrhea Diarrhea is a common problem caused by antibacterial drugs, including LYMEPAK, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, advise patients to contact their physician as soon as possible [see Warnings and Precautions 5.3 ] .

14 CLINICAL STUDIES 14.1 Clinical Trial Experience Doxycycline has been used in clinical practice for early stages of Lyme disease for several decades. Thorough search of the published literature identified 31 studies in which doxycycline treatment was used for the treatment of Lyme disease. Of these 31, three randomized studies evaluating doxycycline treatment in patients with erythema migrans and associated symptoms were identified 1-3 . In addition, two natural history studies of Lyme disease evaluated disease progression in patients presenting with erythema migrans and associated symptoms 4,5 . Over 200 patients from Lyme-disease hyperendemic areas were enrolled in these five studies, and more than 100 received doxycycline. Evidence of efficacy was derived by comparing the doxycycline treatment in studies using doxycycline 100 mg twice daily for 20-21 days with no treatment in the natural history studies. Clinical resolution of symptoms was defined as absence of objective late manifestations of Lyme disease, specifically those related to the musculoskeletal, nervous, and cardiac systems at 6 months. In comparison to untreated patients, doxycycline-treated patients had a higher response rate at 6 months. Doxycycline-treated patients had a response rate of 75-95% compared to 56-66% in untreated patients.

15 REFERENCES Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 1990; 336(8728):1404-1406. Massarotti EM, Luger SW, Rahn DW, Messner RP, Wong JB, Johnson RC et al. Treatment of early Lyme disease. Am J Med 1992; 92(4):396-403. Dattwyler RJ, Luft BJ, Kunkel MJ, Finkel MF, Wormser GP, Rush TJ et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997; 337(5):289-294. Steere AC, Hardin JA, Ruddy S, Mummaw JG, Malawista SE. Lyme arthritis: correlation of serum and cryoglobulin IgM with activity, and serum IgG with remission. Arthritis Rheum 1979b; 22(5):471-483. Steere AC, Malawista SE, Newman JH, Spieler PN, Bartenhagen NH. Antibiotic therapy in Lyme disease. Ann Intern Med 1980; 93(1):1-8.

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.

8.4 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) ].

8.1 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 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding is not recommended ( 8.2 ) 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.

16 HOW SUPPLIED/STORAGE AND HANDLING LYMEPAK tablets contain 100 mg of doxycycline (equivalent to 115 mg doxycycline hyclate). The tablets are green, round, film-coated tablets engraved with LP-1 on one side. NDC # 62135-596-86: is supplied as a child-resistant blister card containing 14 tablets NDC # 62135-596-87: Unit of use carton containing 3 blister cards, total 42 tablets Store at 20°C to 25°C (68°F to 77°F) excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Store at 20°C to 25°C (68°F to 77°F) excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.