Terconazole

Class: Azoles
VA Class: GU300
Chemical Name: cis - 1 - [4 - [2 - (2,4 - Dichlorophenyl) - 2 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]phenyl] - 4 - (1 - methylethyl)piperazine
Molecular Formula: C₂₆H₃₁Cl₂N₅O₃
CAS Number: 67915-31-5
Brands: Terazol

Introduction

Antifungal; azole (triazole derivative).^{1 3 7 8 11 25 28 31}

Uses for Terconazole

Vulvovaginal Candidiasis

Treatment of uncomplicated vulvovaginal candidiasis (mild to moderate, sporadic or infrequent, most likely caused by Candida albicans, occurring in immunocompetent women).^{1 3 5 15 16 17 18 19 20 21 22 23 24 27 33 37 47 49 65 67 68} A drug of choice.^{37 47 51 52 53 54 56 57 58 65 67 68}

Treatment of complicated vulvovaginal candidiasis, including infections that are recurrent (≥4 episodes in 1 year), severe (extensive vulvar erythema, edema, excoriation, fissure formation), caused by Candida other than C. albicans, or occurring in women with underlying medical conditions (uncontrolled diabetes mellitus, HIV infection, immunosuppressive therapy, pregnancy).^{47 53 54 56 57 58 67 68} Complicated infections generally require more prolonged treatment than uncomplicated infections.^{47 66 67 68}

Optimal regimens for treatment of vulvovaginal candidiasis caused by Candida other than C. albicans (e.g., C. glabrata, C. krusei) not identified.^{47 68} CDC and others state these infections may respond to an intravaginal azole antifungal given for 7–14 days or to a 14-day regimen of intravaginal boric acid (not commercially available in the US).^{47 68 69}

Terconazole Dosage and Administration

Administration

Intravaginal Topical Administration

Administer intravaginally as a cream or suppository.¹

Interruption or discontinuance of terconazole therapy during a prescribed regimen, even during menstruation or in response to symptomatic relief, is not advised.^{1 43 44}

Dosage

Adults

Uncomplicated Vulvovaginal Candidiasis

Intravaginal

Cream: one applicatorful of 0.4% cream once daily at bedtime for 7 consecutive days or one applicatorful of 0.8% cream once daily at bedtime for 3 consecutive days.^{1 3 15 47}

Suppository: one 80-mg vaginal suppository once daily at bedtime for 3 consecutive days.^{1 47}

Complicated Vulvovaginal Candidiasis

Recurrent Vulvovaginal Infections Caused by Candida albicans

Intravaginal

CDC and others recommend an initial intensive regimen (7–14 days of an intravaginal azole or 3-dose regimen of oral fluconazole) to achieve mycologic remission, followed by an appropriate maintenance regimen (6-month regimen of once-weekly oral fluconazole or, alternatively, an intravaginal azole given intermittently).^{47 52 54 58 64 67 68}

Other Complicated Vulvovaginal Infections

Intravaginal

CDC and others recommend 7–14 days of an intravaginal azole for vulvovaginal candidiasis that is severe, caused by Candida other than C. albicans, or occurring in women with underlying medical conditions.^{47 67}

HIV-infected patients: Use same regimen recommended for other patients.^{47 66} Some experts recommend a duration of 3–7 days.⁶⁶ Maintenance regimen of an intravaginal azole can be considered for those with recurrent episodes;⁶⁶ routine primary or secondary prophylaxis (long-term suppressive or chronic maintenance therapy) not recommended.^{47 66}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^a

Renal Impairment

No specific dosage recommendations at this time.^a

Geriatric Patients

No specific dosage recommendations at this time.^a

Cautions for Terconazole

Contraindications

• 
  

  Known hypersensitivity to terconazole or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Sensitivity Reactions

Allergic Reactions

Possible flu-like syndrome, characterized by fever, chills, headache, and/or hypotension and occasionally by vertigo and nausea.⁴⁵ May be immunoallergenic⁴⁵ or may be a reaction to the dying fungi (similar to the Jarisch-Herxheimer reaction observed during penicillin therapy for syphilis).⁴⁶

If irritation, sensitization, fever, chills, or flu-like symptoms occur and appear to be drug related, discontinue and do not reinstitute terconazole therapy.¹

Photosensitivity Reactions

Photosensitivity reactions reported following repeated topical application to the skin of 0.8 or 2% terconazole cream and exposure to filtered artificial ultraviolet light; not reported to date following intravaginal administration of 0.4 or 0.8% cream or 80-mg suppositories.^{1 3}

General Precautions

Use of Latex/Rubber Contraceptive Diaphragms

Hydrogenated vegetable oil base contained in terconazole vaginal suppositories may interact with certain rubber or latex products such as vaginal contraceptive diaphragms; concurrent use not recommended.¹ Consider use of terconazole vaginal cream as an alternative to the suppositories.^{43 44}

Selection and Use of Antifungals for Vulvovaginal Candidiasis

Prior to initial use of terconazole in a woman with signs and symptoms of vulvovaginal candidiasis, confirm the diagnosis by demonstrating yeast or pseudohyphae with direct microscopic examination of vaginal discharge (saline or 10% potassium hydroxide [KOH] wet mount or Gram stain) or by culture.^{1 47}

Candida identified by culture in the absence of symptoms is not an indication for antifungal treatment since approximately 10–20% of women harbor Candida or other yeasts in the vagina.⁴⁷

If clinical symptoms persist, tests should be repeated to rule out other pathogens and to confirm the original diagnosis.¹

Specific Populations

Pregnancy

Category C.¹

Because terconazole is absorbed systemically following intravaginal administration, manufacturer states the drug should not be used during the first trimester of pregnancy unless the clinician considers it essential to the welfare of the patient.¹ CDC and others state that a 7-day regimen of an intravaginal azole antifungal can be used, if necessary, for treatment of vulvovaginal candidiasis in pregnant women.^{47 67}

Lactation

Distributed into milk in rats;¹ not known whether distributed into human milk.^{1 43} Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children¹ <18 years of age.⁴³

Geriatric Use

Insufficient experience from clinical studies to determine whether patients ≥65 years of age respond differently than younger adults.¹ Other clinical experience has not identified age-related differences in response.¹

Common Adverse Effects

Headache,^{1 3} vulvovaginal itching/burning or pain,^{1 3} dysmenorrhea,¹ abdominal pain.¹

Interactions for Terconazole

Oral Contraceptives

Terconazole efficacy not affected by concomitant oral contraceptives; terconazole has no effect on estradiol or progesterone concentrations in women receiving low-dose oral contraceptives.^{1 5}

Terconazole Pharmacokinetics

Absorption

Small amounts of terconazole (about 5–16% of a dose) are slowly absorbed systemically following intravaginal administration.^{1 3 14} The amount of drug absorbed is proportional to the dose (regardless of dosage form)^{3 14} and absorption is similar in women with or without vulvovaginal candidiasis.³

Distribution

Extent

Distribution into body tissues and fluids following intravaginal administration has not been determined.^a

Not known whether terconazole crosses the placenta⁴³ or is distributed into milk.¹

Elimination

Metabolism

The metabolic fate of terconazole following intravaginal administration has not been fully characterized, but systemically absorbed drug appears to be rapidly and extensively metabolized.^{1 3}

Elimination Route

Following oral administration, 32–56% of the dose excreted in urine and 47–52% excreted in feces¹ within 24 hours.⁴³

Half-life

Following oral administration, half-life is 6.9 hours.¹

Stability

Storage

Cream

15–30°C.¹

Suppository

15–30°C.¹

ActionsActions

• 
  

  Triazole-derivative azole antifungal.^{1 3 5 7 8 10 11 12 14 15 18 19 21 25 27 28 29 31 33 34 35}

  
  


• 
  

  Usually fungicidal in action.^{1 3 7 11}

  
  


• 
  

  Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA).^{3 4 8 12 34} Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.^{3 4 6 8 12 28 34}

  
  


• 
  

  Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.^{3 7 8 10 11 12 14 15 31} At high concentrations, has some in vitro activity against gram-positive and -negative bacteria.^{7 11 25 31 34}

  
  


• 
  

  Candida: Active in vitro and in vivo against C. albicans,^{3 8 11 31 32} C. krusei,^{3 8 11} C. parapsilosis,⁸ C. pseudotropicalis,⁸ C. stellatoidea,⁸ and C. tropicalis.^{3 8 11 31}

  
  


• 
  

  Dermatophytes and other fungi: Active in vitro against Trichophyton mentagrophytes,^{3 11 31} T. rubrum,^{3 11 31} T. tonsurans,^{3 11} T. verrucosum,^{3 11} and Epidermophyton floccosum.^{3 11} Also active against Cryptococcus neoformans.^{3 11 31}

  
  


• 
  

  Cross resistance can occur among the azole antifungals (e.g., clotrimazole, ketoconazole, miconazole).^{9 47} Azole-resistant Candida have been reported.^{9 47}

  
  

Advice to Patients

• 
  

  Importance of reading and understanding manufacturer’s patient instructions regarding use of applicator for intravaginal administration.¹

  
  


• 
  

  Importance of not interrupting or discontinuing the drug and completing full course of therapy, even during menstruation or in response to symptomatic relief.^{1 43 44}

  
  


• 
  

  Importance of informing clinicians if irritation, sensitization, fever, chills, or flu-like symptoms occur.¹

  
  


• 
  

  Importance of women following clinician's advice regarding sexual intercourse and informing partner to seek medical advice if penile itching, redness, or discomfort occurs.¹

  
  


• 
  

  Importance of not using rubber or latex products such as vaginal contraceptive diaphragms when using terconazole vaginal suppositories;¹ use of terconazole vaginal cream should be considered as an alternative.^{43 44}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Terconazole

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Vaginal	Cream	0.4%*	Terazol 7 (with propylene glycol; with applicator)	Ortho-McNeil
			Terconazole Vaginal Cream	Taro, Watson
		0.8%*	Terazol 3 (with propylene glycol; with applicator)	Ortho-McNeil
			Terconazole Vaginal Cream	Taro, Watson
	Suppositories	80 mg*	Terazol 3 (in a hydrogenated vegetable oil base; with applicator)	Ortho-McNeil
			Terconazole Vaginal Suppositories (in a hydrogenated vegetable oil base; with applicator)	Perrigo

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Terazol 3 0.8% Cream (ORTHO-MCNEIL PHARMACEUTICAL): 20/$51.99 or 60/$149.98

Terazol 3 80MG Suppositories (ORTHO-MCNEIL PHARMACEUTICAL): 3/$53.99 or 9/$149.98

Terazol 7 0.4% Cream (ORTHO-MCNEIL PHARMACEUTICAL): 45/$53.99 or 135/$147.98

Terconazole 0.4% Cream (WATSON LABS): 45/$39.99 or 135/$109.97

Terconazole 0.8% Cream (WATSON LABS): 20/$34.99 or 60/$94.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ortho-McNeil Pharmaceutical, Inc. Terazol 7 (terconazole) vaginal cream 0.4%, Terazol 3 (terconazole) vaginal cream 0.8%, and Terazol 3 (terconazole) vaginal suppositories prescribing information. Raritan, NJ; 2003 Apr.

3. Ortho Pharmaceutical Corporation. Terazol (terconazole 0.4% cream/80 mg suppositories) clinical monograph. Raritan, NJ; 1988 Jun.

4. Wilborn WH, Shields RL, Hyde BM et al. Mode of action of terconazole on Candida albicans as shown by scanning and transmission electron microscopy during treatment for vulvovaginal candidiasis. Am J Gynecol Health. 1988; 2:51-6.

5. Kjaeldgaard A, Larsson B. Single-blind comparative clinical trial of short-term therapy with terconazole versus clotrimazole vaginal tablets in vulvovaginal candidiasis. Curr Ther Res Clin Exp. 1985; 38:939-44.

6. Borgers M, Van den Bossche H, De Brabander M. The mechanism of action of the new antimycotic ketoconazole. Am J Med. 1983; 74(Suppl 1B):2-8. [IDIS 165048] [PubMed 6295147]

7. Isaacson DM, Foleno B, Tolman EL et al. In vitro studies with terconazole. Gynakol Rundsch. 1985; 25(Suppl 1):12-25. [PubMed 3891537]

8. Tolman EL, Isaacson DM, Rosenthale ME et al. Anticandidal activities of terconazole, a broad-spectrum antimycotic. Antimicrob Agents Chemother. 1986; 29:986-91. [PubMed 3729366]

9. Smith KJ, Warnock DW, Kennedy CTC et al. Azole resistance in Candida albicans. J Med Vet Mycol. 1986; 24:133-44. [PubMed 3014106]

10. Cauwenbergh G. New and prospective developments in antifungal drugs. Acta Derm Venereol. 1986; 121(Suppl):147-53.

11. Van Cutsem J, Van Gerven F, Zaman R et al. Terconazole—a new broad-spectrum antifungal. Chemotherapy. 1983; 29:322-31. [PubMed 6617296]

12. Isaacson DM, Tolman EL, Tobia AJ et al. Selective inhibition of 14α-desmethyl sterol synthesis in Candida albicans by terconazole, a new triazole antimycotic. J Antimicrob Chemother. 1988; 21:333-43. [PubMed 3129389]

13. Turner CA, Turner A, Warnock DW. High performance liquid chromatographic determination of ketoconazole in human serum. J Antimicrob Chemother. 1986; 18:757-63. [PubMed 3546244]

14. Kennedy BK, Friedmann N. Terconazole cream and suppositories: plasma terconazole following vaginal administration. Gynakol Rundsch. 1985; 25(Suppl 1):26-32. [PubMed 4007621]

15. Del Palacio-Hernanz, Sanz-Sanz F, Rodriquez-Noriega A. Double-blind investigation of R-42470 (terconazole cream 0.4%) and clotrimazole (cream 1%) for the topical treatment of mycotic vaginitis. Chemioterapia. 1984; 3:192-5. [PubMed 6529776]

16. Loendersloot EW. Demonstration of effectiveness and tolerability of terconazole 80-mg vaginal suppositories (3 days) versus terconazole 240-mg vaginal suppositories (1 day) versus clotrimazole 200-mg vaginal tablets (3 days) in non-pregnant women with vulvovaginal candidosis. Gynakol Rundsch. 1985; 25(Suppl 1):99-104. [PubMed 4007627]

17. Munnich W, Hiltl BP. Single-day topical treatment of vaginal candidosis: an open evaluation of terconazole 240-mg vaginal suppositories versus isoconazole tablets 600 mg. Gynakol Rundsch. 1985; 25(Suppl 1):90-8. [PubMed 4007626]

18. Grice G, Spencer RC, Steele CE et al. One-day treatment of vaginal candidosis: comparison of terconazole 240-mg suppository with clotrimazole 500-mg vaginal tablet. Gynakol Rundsch. 1985; 25(Suppl 1):83-9. [PubMed 3891541]

19. Goormans E. Comparative double-blind evaluation of the efficacy and tolerability of terconazole 240-mg suppository (1 day) and 80-mg suppositories (3 days) versus clotrimazole 200-mg (3 days) in pregnant patients with vulvovaginal candidosis. Gynakol Rundsch. 1985; 25(Suppl 1):74-82. [PubMed 3891540]

20. Wesel S, Benijts G, Ubachs JMH et al. Comparative open evaluation of efficacy and tolerability of terconazole 0.8% cream in a 5-day regimen versus clotrimazole 100-mg tablets in a 6-day regimen. Gynakol Rundsch. 1985; 25(Suppl 1):67-73. [PubMed 4007625]

21. Litschgi M. Assessment of clinical efficacy and tolerability of terconazole 240-mg vaginal suppositories. Gynakol Rundsch. 1985; 25(Suppl 1): 59-66. [PubMed 4007623]

22. Nahmanovici C. Treatment of vaginal candidosis with three 80-mg terconazole vaginal suppositories: results of a multicentre study in France. Gynakol Rundsch. 1985; 25(Suppl 1):52-8. [PubMed 3891539]

23. Delecour M. Advantages of a 6- to 7-day treatment with 40-mg vaginal suppositories of terconazole against vaginal candidosis: conclusions drawn from a phase II multicentre study in France. Gynakol Rundsch. 1985; 25(Suppl 1):42-51. [PubMed 3891538]

24. Siedentopf HG. Terconazole 0.8% vaginal cream (5 days) versus clotrimazole 1% (6 days): efficacy and tolerability in an open study. Gynakol Rundsch. 1985; 25(Suppl 1):33-41. [PubMed 4007622]

25. Cartwright RY. Terconazole, a new triazole antifungal agent. Gynakol Rundsch. 1985; 25(Suppl 1):6-11. [PubMed 4007624]

26. Hirsch HA. Vulvovaginal candidosis: definition of the disease and its special problems and treatment in pregnancy. Gynakol Rundsch. 1985; 25(Suppl 1):1-5. [PubMed 4007619]

27. Martinek G. Summary of clinical studies with vaginal formulations of terconazole. Gynakol Rundsch. 1985; 25(Suppl 1):105-13. [PubMed 3891536]

28. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrob Agents Chemother. 1988; 32:1-8. [IDIS 243869] [PubMed 2831809]

29. Holmberg K. In vitro assessment of antifungal drug resistance. Acta Derm Venereol. 1986; 121:131-8.

30. Odds FC, Cheesman SL, Abbott AB. Suppression of ATP in Candida albicans by imidazole and derivative antifungal agents. Sabouraudia. 1985; 23:415-24. [PubMed 3913012]

31. Heeres J, Hendrickx R, Van Cutsem J. Antimycotic azoles: 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal. J Med Chem. 1983; 26:611-3. [PubMed 6834396]

32. Odds FC, Webster CE, Abbott AB. Antifungal relative inhibition factors: BAY 1-9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents. J Antimicrob Chemother. 1984; 14:105-14. [PubMed 6094418]

33. Vartiainen E, Widholm O. Single-dose therapy of vulvovaginal candidosis: comparison of terconazole and clotrimazole. Curr Ther Res. 1988; 44:185-8.

34. Vanden Bossche H, Lauwers W, Willemsens G et al. Molecular basis for the antimycotic and antibacterial activity of N-substituted imidazoles and triazoles: the inhibition of isoprenoid biosynthesis. Pestic Sci. 1984; 15:188-98.

35. Anon. Discussion. Gynakol Rundsch. 1985; 25(Suppl 1):114-7. [PubMed 4007620]

36. Hay RJ. Recent advances in the management of fungal infections. Quarterly J Med. 1987; 64(No. 244):631-9.

37. Anon. Drugs for sexually transmitted diseases. Treat Guidel Med Lett. 2004; 2:67-74. [PubMed 15529116]

38. Thomas AH. Suggested mechanisms for the antimycotic activity of the polyene antibiotics and the N-substituted imidazoles. J Antimicrob Chemother. 1986; 17:269-79. [PubMed 3516967]

39. Beggs WH, Andrews FA, Sarosi GA. Minireview: action of imidazole-containing antifungal drugs. Life Sci. 1981; 28:111-8. [PubMed 7019609]

40. Borgers M. Mechanism of action of antifungal drugs, with special reference to the imidazole derivatives. Rev Infect Dis. 1980; 2:520-34. [IDIS 124096] [PubMed 7003674]

41. Sud IJ, Feingold DS. Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol. 1981; 76:438-41. [IDIS 133194] [PubMed 7017013]

42. Pye GW, Marriott. Inhibition of sterol C14 demethylation by imidazole-containing antifungals. Sabouraudia. 1982; 20:325-9. [PubMed 6760419]

43. Murphy RJ. (Ortho Pharmaceutical Corporation, Raritan, NJ): Personal communication; 1988 Dec.

44. Reviewers’ comments (personal observations); 1988 Dec.

45. Moebius UM. Influenza-like syndrome after terconazole. Lancet. 2:966-7. Letter.

46. Geiger AJ. Influenza-like syndrome after terconazole. Lancet. 1988; 2:1192. [IDIS 248142] [PubMed 2903397]

47. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55(No. RR-11):1-96.

49. Doering PL, Santiago TM. Drugs for treatment of vulvovaginal candidiasis: comparative efficacy of agents and regimens. DICP. 1990; 24:1078-83. [IDIS 274670] [PubMed 2275233]

50. Sobel JD. Pathogenesis and treatment of recurrent vulvovaginal candidiasis. Clin Infect Dis. 1992; 14(Suppl 1):S148-53.

51. Hay RJ. Yeast infections. Dermatol Clin. 1996; 14:113-24. [PubMed 8821164]

52. Doering PL, Santiago TM. Drugs for the treatment of vulvovaginal candidiasis: comparative efficacy of agents and regimens. DICP. 1990; 24:1078-83. [IDIS 274670] [PubMed 2275233]

53. Sobel JD. Vaginitis. N Engl J Med. 1997; 337:1896-903. [IDIS 401347] [PubMed 9407158]

54. Sobel JD, Faro S, Force RW et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol. 1998; 178:203-11. [IDIS 402301] [PubMed 9500475]

55. Bisschop MPJM, Merkus JMWM, Scheygrond H et al. Co-treatment of the male partner in vaginal candidosis: a double-blind randomized control study. Br J Obstet Gynecol. 1986; 93:79-81.

56. Bohannon NJV. Treatment of vulvovaginal candidiasis in patients with diabetes. Diabetes Care. 1998; 21:451-6. [IDIS 402373] [PubMed 9540031]

57. Tobin MJ. Vulvovaginal candidiasis: topical vs. oral therapy. Am Fam Physician. 1995; 51:1715-24. [IDIS 348350] [PubMed 7754931]

58. Sobel JD. Controversial aspects in the management of vulvovaginal candidiasis. J Am Acad Dermatol. 1994; 31: S10-3. [IDIS 335764] [PubMed 8077494]

59. Spinillo A, Capuzzo E, Gulminetti R et al. Prevalence of and risk factors for fungal vaginitis caused by non-albicans species. Am J Obstet Gynecol. 1997; 176: 138-41. [PubMed 9024104]

60. Chaim W. Fungal vaginitis caused by nonalbicans species. Am J Obstet Gynecol. 1997; 177: 485. [IDIS 393344] [PubMed 9290485]

61. Spinillo A, Capuzzo E. Fungal vaginitis caused by nonalbicans species. Am J Obstet Gynecol. 1997; 177: 485-6.

62. Redondo-Lopez V, Lynch M, Schmitt C et al. Torulopsis glabrata vaginitis: clinical aspects and susceptibility to antifungal agents. Obstet Gynecol. 1990; 76: 651-5.

63. Sobel JD. Pathogenesis and treatment of recurrent vulvovaginal candidiasis. Clin Infect Dis. 1992; 14(Suppl 1):S148-53.

64. Reviewers’ comments (personal observations) on Tioconazole 84:04.08.

65. Anon. Drugs for vulvovaginal candidiasis. Med Lett Drugs Ther. 2001; 43:3-4. [PubMed 11151090]

66. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

67. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 72, May 2006: vaginitis. Obste Gynecol. 2006; 107:1195-296.

68. Pappas GP, Rex JR, Sobel JD et al. Guidelines for treatment of candidiasis. Clin Infect Ids. 2004; 38:161-89.

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a. AHFS drug information 2003. McEvoy GK, ed. Terconazole. Bethesda, MD: American Society of Health-System Pharmacists; 2003:3365-69.

More Terconazole resources

• Terconazole Side Effects (in more detail)
• Terconazole Use in Pregnancy & Breastfeeding
• Terconazole Support Group
• 6 Reviews for Terconazole - Add your own review/rating

• Terazol 3 Suppositories MedFacts Consumer Leaflet (Wolters Kluwer)


• Terazol 3 Concise Consumer Information (Cerner Multum)


• Terazol 7 Prescribing Information (FDA)


• Zazole Prescribing Information (FDA)


• Zazole Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Terconazole with other medications

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Cimetidine 200mg / 5ml Oral Solution

Cimetidine 200mg/5ml Oral Solution

• 
  Read all of this leaflet carefully before you start taking this medicine
  


• Keep this leaflet. You may need to read it again


• If you have any further questions, ask your doctor or your pharmacist


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours


• If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet

• 1. What is Cimetidine Oral Solution and what is it used for


• 2. Before you take Cimetidine Oral Solution


• 3. How to take Cimetidine Oral Solution


• 4. Possible side effects


• 5. How to store Cimetidine Oral Solution


• 6. Further information

What is Cimetidine Oral Solution and what is it used for

The name of your medicine is Cimetidine 200mg/5ml Oral Solution. It contains cimetidine. This belongs to a group of medicines called H₂ antagonists, which reduce the amount of acid in your stomach.

This medicine is used to:

• heal and stop ulcers in the stomach, or the part it empties into, the duodenum


• heal and stop problems caused by acid in the gullet (oesophagus) or too much acid in the stomach. This can cause pain or discomfort known as indigestion or heartburn


• prevent ulcers from bleeding


• prevent ulcers which may be caused by medicines called non-steroidal anti-inflammatories (NSAIDs), often used to treat arthritis


• improve absorption of food and reduce fluid loss in short bowel syndrome


• be given before an operation to prevent acid coming up from the stomach whilst under anaesthetic.

Before you take Cimetidine Oral Solution

Do not take Cimetidine Oral Solution and tell your doctor if:

• you are allergic (hypersensitive) to cimetidine or any other ingredients in this liquid (listed in Section 6)
  
  
  The signs of an allergic reaction include a rash, itching or shortness of breath


• you are pregnant, likely to become pregnant and if you are breast-feeding.

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking cimetidine.

Take special care with Cimetidine Oral Solution

Before you take cimetidine, tell your doctor if:

• you have kidney problems


• you have lost weight recently and also have stomach ache, stomach pain or indigestion at the same time, particularly if you are over 40.

You should see your doctor regularly especially if you are taking Cimetidine Oral Solution as well as medicine for arthritis. This is particularly important in the elderly or those with a history of ulcers.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking cimetidine.

Going into hospital

Do not take this medicine if you are going into hospital today for an operation or to give birth.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because cimetidine can affect the way some other medicines work. Also some medicines can affect the way cimetidine works.

Tell your doctor if you are taking any of these medicines

• non-steroidal anti-inflammatories (NSAIDs) e.g. indometacin, aspirin


• phenytoin used for epilepsy


• medicines to stop the blood clotting such as warfarin


• theophylline used for asthma


• lidocaine


• medicines that cause a fall in blood cell count.

Pregnancy and breast-feeding

• Talk to your doctor before taking this medicine if you are pregnant, planning to become pregnant or are breast-feeding. Cimetidine should not be used when you are pregnant or breast feeding unless the doctor considers it necessary


• Do not take this medicine if you are in labour.

Driving and using machines

This product should not affect your ability to drive or to use machinery.

Important information about what is in Cimetidine Oral Solution

This medicine contains:

• methyl and propyl parahydroxybenzoates. These may cause an allergic reaction. This allergy may happen some time after starting the medicine


• liquid maltitol. If your doctor has told you that you cannot tolerate some sugars, see your doctor before taking this medicine


• sunset yellow E110. This may cause an allergic reaction including asthma.


• propylene glycol which may cause alcohol-like symptoms.

How to take Cimetidine Oral Solution

Take this medicine as your doctor or pharmacist has told you. Look on the label and ask the doctor or pharmacist if you are not sure.

Taking this medicine

• This medicine contains 200mg of cimetidine in each 5ml


• Take this medicine by mouth


• The total daily dose should not be more than 2.4g each day


• The usual length of treatment is 4 weeks.

Adults and older people

The usual doses for adults are given below:

• The usual dose is 400mg (two 5ml spoonfuls) at breakfast and at bedtime. This may be altered by your doctor depending upon what this medicine is being prescribed for.

Children above 1 year old

If prescribed for a child, the dosage depends on the child’s weight. Make sure the child takes the liquid as the doctor says. The usual dose is 25-30mg/Kg body weight each day.

The dose should not be more than 2.4g each day.

People with severe kidney problems

The dose may be lowered if you have kidney problems as you may be more sensitive to the effects of the medicine.

If you take more Cimetidine Oral Solution than you should

Talk to a doctor or go to a hospital straight away. Take the medicine pack with you so the doctor knows what you have taken.

If you forget to take Cimetidine Oral Solution

Do not take a double dose (two doses at the same time) to make up for forgotten doses. Skip the missed dose, then go on as before.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, cimetidine can cause side effects, although not everybody gets them.

If you have an allergic reaction to this medicine, STOP taking the medicine and see a doctor immediately.

An allergic reaction may include:

• any kind of skin rash or “hives”, flaking skin, boils or sore lips, swelling (of the face, eyelids, lips, mouth or tongue), fever, swollen blood vessels


• sudden wheezing, fluttering or tightness of the chest, chest pain, feeling faint especially when standing up or collapse.

If you get any of the following side effects, see your doctor as soon as possible:

• unusual tiredness, shortness of breath, bruising more easily or other signs of infection – this could be a sign of blood problems


• stomach and back pain, fever, feeling or being sick – this may be a sign that your pancreas is swollen


• hepatitis. You may notice symptoms such as a tender stomach and abdomen, loss of appetite and yellowing of the skin and the whites of the eyes (jaundice)


• irregular or slow heart beats


• feeling depressed or confused.

Tell your doctor if you get any of these side effects:

• diarrhoea


• feeling tired


• breast swelling in men and impotence


• headache, fever and dizziness


• hallucinations (seeing or hearing things that are not there)


• hair loss


• skin rash


• joint or muscle pain.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.

How to store Cimetidine Oral Solution

• Keep out of the reach and sight of children


• Do not store above 25°C and keep out of direct sunlight


• Do not use 1 month from the date you first open it


• Do not use after the expiry date which is stated on the label and carton (exp: month, year)


• The expiry date refers to the last day of that month


• Do not use Cimetidine Oral Solution if you notice that the appearance or smell of your medicine has changed. Talk to your pharmacist


• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Cimetidine Oral Solution contains

• The active ingredient is cimetidine


• The other ingredients are methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), propylene glycol (E1520), liquid maltitol (E965) (containing sorbitol), hydrochloric acid, disodium hydrogen phosphate (E339), saccharin sodium, ammonium glycyrrhizinate, peach and peppermint flavour (containing propylene glycol), sunset yellow (E110) and purified water.

What Cimetidine Oral Solution looks like and contents of the pack

A clear yellow/orange liquid with an odour of peppermint and peach

It comes in a brown glass bottle holding 300ml of solution.

Marketing Authorisation Holder and Manufacturer

Rosemont Pharmaceuticals Ltd

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

This leaflet was last approved in September 2009

P0480

Mirapex ER

Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION

1   INDICATIONS AND USAGE

Mirapex ER® tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

2   DOSAGE AND ADMINISTRATION

   General Dosing Considerations

Mirapex ER tablets are taken orally once daily, with or without food.

Mirapex ER tablets must be swallowed whole and must not be chewed, crushed, or divided.

If a significant interruption in therapy with Mirapex ER tablets has occurred, re-titration of therapy may be warranted.

   Dosing for Parkinson's Disease

The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day.

In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Clinical Studies (14)].

Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [see Clinical Studies (14)].

When discontinuing therapy with Mirapex ER, taper the dose gradually over a period of one week. In some studies with immediate-release pramipexole tablets, however, abrupt discontinuation was uneventful.

Dosing in Patients with Renal Impairment

The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose.

In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), Mirapex ER tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals.

Mirapex ER tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients.

   Switching from Immediate-Release Pramipexole Tablets to Mirapex ER

Patients may be switched overnight from immediate-release pramipexole tablets to Mirapex ER tablets at the same daily dose. When switching between immediate-release pramipexole tablets and Mirapex ER tablets, patients should be monitored to determine if dosage adjustment is necessary.

3   DOSAGE FORMS AND STRENGTHS

0.375 mg white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.375" on the other side

0.75 mg white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.75" on the other side

1.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "1.5" on the other side

2.25 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "2.25" on the other side

3 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.0" on the other side

3.75 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.75" on the other side

4.5 mg white to off-white, oval, extended-release tablets debossed with "ER" on one side and "4.5" on the other side

4   CONTRAINDICATIONS

None.

5   WARNINGS AND PRECAUTIONS

   Falling Asleep During Activities of Daily Living

Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with Mirapex ER tablets compared to 2 of 281 (1%) patients on placebo.

In early Parkinson’s disease, somnolence was reported in 36% of 223 patients treated with Mirapex ER, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson’s disease, somnolence was reported in 15% of 164 patients treated with Mirapex ER tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with Mirapex ER tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Mirapex ER tablets should ordinarily be discontinued. If a decision is made to continue Mirapex ER tablets, advise patients not to drive and to avoid other potentially dangerous activities. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

   Symptomatic Orthostatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists, including Mirapex ER, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk [see Patient Counseling Information (17.5)]. In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with Mirapex ER tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on Mirapex ER tablets discontinued treatment due to hypotension.

   Impulse Control/Compulsive Behaviors

Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Mirapex ER, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Mirapex ER. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Mirapex ER [see Patient Counseling Information (17.3)].

A total of 1056 patients with Parkinson’s disease who participated in two Mirapex ER placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with Mirapex ER tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

   Hallucinations

In placebo-controlled clinical trials in Parkinson's disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with Mirapex ER tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on Mirapex ER tablets.

Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%) patients ≥65 years of age taking Mirapex ER tablets compared to 10 of 225 (4%) patients <65 years of age taking Mirapex ER tablets.

   Dyskinesia

Mirapex ER tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

   Renal Impairment

The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Mirapex ER tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

   Rhabdomyolysis

In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

   Retinal Pathology in Rat

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved [see Nonclinical Toxicology (13.2)].

   Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Withdrawal-Emergent Hyperpyrexia and Confusion

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

Melanoma

Epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Mirapex ER tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

6  ADVERSE REACTIONS

The following are discussed in greater detail in other sections of the labeling:

• Falling Asleep During Activities of Daily Living [see Warnings and Precautions (5.1)]


• Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2)]


• Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.3)]


• Hallucinations [see Warnings and Precautions (5.4)]


• Dyskinesia [see Warnings and Precautions (5.5)]


• Renal Impairment [see Warnings and Precautions (5.6)]


• Rhabdomyolysis [see Warnings and Precautions (5.7)]


• Retinal Pathology in Rat [see Warnings and Precautions (5.8)]


• Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.9)]

   Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

During the premarketing development of Mirapex ER tablets, patients with early Parkinson's disease were treated with Mirapex ER tablets, placebo, or immediate-release pramipexole tablets. In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to Mirapex ER tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed. In a third trial, advanced Parkinson’s disease patients received Mirapex ER tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa.

Early Parkinson's Disease

The most commonly observed adverse events (≥5% and more frequent than placebo) after 33 weeks of treatment with Mirapex ER tablets in the trial of early Parkinson’s disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.

Twenty four of 223 (11%) patients treated with Mirapex ER tablets for 33 weeks discontinued treatment due to adverse events compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse event most commonly causing discontinuation of treatment with Mirapex ER tablets was nausea (2%).

Table 1 lists adverse events that occurred with a frequency of at least 2% with Mirapex ER and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease. In this study, patients did not receive concomitant levodopa; however, levodopa was permitted as rescue medication. Adverse events were usually mild (38%) or moderate (41%) in intensity.

Table 1  Treatment-Emergent Adverse-Event Incidence in a Double-Blind, Placebo-Controlled 33 Week Trial in Early Parkinson’s Disease (Events ≥2% of Patients Treated with Mirapex ER and greater than with Placebo)

Body System/Adverse Event	Placebo	Mirapex ER	Immediate-Release Pramipexole
	(n=103)	(n=223)	(n=213)
	%	%	%
Nervous system disorders
Somnolence	15	36	33
Dizziness	7	12	12
Tremor	1	3	3
Balance disorder	1	2	0
Gastrointestinal disorders
Nausea	9	22	24
Constipation	2	14	12
Dry mouth	1	5	4
Vomiting	0	4	4
Upper abdominal pain	1	3	4
Dyspepsia	2	3	3
Abdominal discomfort	0	2	1
General disorders and administration site conditions
Fatigue	4	6	6
Peripheral edema	4	5	8
Asthenia	2	3	1
Musculoskeletal and connective tissue disorders
Muscle spasms	3	5	3
Psychiatric disorders
Hallucinations, including visual, auditory and mixed	1	5	6
Insomnia	3	4	4
Sleep attacks or sudden onset of sleep	1	3	6
Sleep disorder	1	2	3
Depression	0	2	0
Injury, poisoning and procedural complications
Fall	1	4	4
Vascular disorders
Orthostatic hypotension	1	3	0
Ear and labyrinth disorders
Vertigo	1	4	2
Metabolism and nutrition disorders
Increased appetite	1	3	2
Respiratory, thoracic and mediastinal disorders
Cough	1	3	3

Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse events.

Adverse events can initially occur in either the titration or maintenance phase.  Some adverse events developed in Mirapex ER-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., Mirapex ER % - placebo % = treatment difference ≥2%); persistent adverse events were somnolence, nausea, constipation, fatigue, and dry mouth.

A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight switch from immediate-release pramipexole tablets to Mirapex ER tablets at the same daily dose in 156 early Parkinson’s disease patients with or without levodopa. One of 104 patients switched from immediate-release pramipexole tablets to Mirapex ER tablets discontinued due to adverse events (vertigo and nausea).

Advanced Parkinson's Disease

The most commonly observed adverse events (≥5% and greater frequency than in placebo) during 18 weeks of treatment with Mirapex ER tablets in the trial of advanced Parkinson’s disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia.

Eight of 164 (5%) patients treated with Mirapex ER tablets for 18 weeks discontinued treatment due to adverse events compared to 7 of 178 (4%) patients who received placebo and 8 of 175 (5%) patients who received immediate-release pramipexole tablets. The most common adverse events leading to discontinuation of treatment with Mirapex ER tablets were nausea (1%) and hallucination (1%).

Table 2 lists adverse events that occurred with a frequency of at least 2% with Mirapex ER and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson’s disease treated with Mirapex ER tablets. In this study, Mirapex ER tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa. Adverse events were usually mild (32%) or moderate (17%) in intensity.

Table 2 Treatment-Emergent Adverse-Event Incidence in a Double-Blind, Placebo-Controlled Trial in Advanced Parkinson’s Disease* (Events ≥2% of Patients Treated with Mirapex ER and greater than with Placebo)

Body System/Adverse Event	Placebo	Mirapex ER	Immediate-Release Pramipexole
	n=178	n=164	n=175
	%	%	%
*18-week final analysis
Nervous system disorders
Dyskinesia	8	17	18
Headache	3	7	4
Dizziness (postural)	1	2	3
Gastrointestinal disorders
Nausea	10	11	11
Constipation	5	7	6
Salivary hypersecretion	0	2	0
Diarrhea	1	2	1
Psychiatric disorders
Hallucinations, including visual, auditory and mixed	2	9	7
Insomnia	2	4	4
Metabolism and nutrition disorders
Anorexia	2	5	1
Musculoskeletal and connective tissue disorders
Back pain	1	2	3

Because this flexible dose study used a titration design, it was not possible to assess the effects of dose on the incidence of adverse events.

Adverse events can initially occur in either the titration or maintenance phase. Some adverse events developed in Mirapex ER-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., Mirapex ER % - placebo % = treatment difference ≥2%); persistent adverse events were dyskinesia and insomnia.

Laboratory Testing

During the development of Mirapex ER tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.

Other adverse events observed during clinical trials of immediate-release pramipexole tablets

Adverse events not listed above but reported on at least two occasions (one occasion if the event was serious) in clinical studies involving 2509 individuals who received pramipexole immediate-release tablets are listed below. The reported events are included without regard to determination of a causal relationship to pramipexole immediate-release tablets.

Blood and lymphatic system disorders: anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia

Cardiac disorders: angina pectoris, arrhythmia supraventricular, atrial fibrillation, atrioventricular block first degree, atrioventricular block second degree, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac failure congestive, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy

Congenital, familial, and genetic disorders: atrial septal defect, congenital foot malformation, spine malformation

Ear and labyrinth disorders: deafness, ear pain, hearing impaired, hypoacusis, motion sickness, vestibular ataxia

Endocrine disorders: goiter, hyperthyroidism, hypothyroidism

Eye disorders: accommodation abnormalities, amaurosis fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, diplopia, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma, vision abnormalities, vision blurred, visual acuity reduced, vitreous floaters

Gastrointestinal disorders: abdominal distension, aphthous stomatitis, ascites, cheilitis, colitis, colitis ulcerative, dyspepsia, dysphagia, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage, gastroesophageal reflux disease, gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus, inguinal hernia, intestinal obstruction, irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia

General disorders: chest discomfort, chills, death, drug withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, fever, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, malaise, pitting edema, thirst

Hepatobiliary disorders: biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis

Immune system disorders: drug hypersensitivity

Infections and infestations: abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, influenza, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection

Injury, poisoning, and procedural complications: accidental falls, drug toxicity epicondylitis, road traffic accident, sunburn, tendon rupture

Metabolism and nutrition disorders: cachexia, decreased appetite, decreased weight, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased creatine PK, metabolic alkalosis

Musculoskeletal and connective tissue disorders: bone pain, bursitis, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, musculoskeletal stiffness, myasthenia, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, pain in extremity, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis, twitching

Neoplasms benign, malignant, and unspecified: abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma

Nervous system disorders: ageusia, akinesia, amnesia, akathisia, anticholinergic syndrome, aphasia, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, dystonia, extrapyramidal syndrome, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypertonia, hypesthesia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, myoclonus, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, syncope vasovagal, tension headache, thinking abnormalities

Psychiatric disorders: affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusions, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, paranoid reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation

Renal and urinary disorders: chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary frequency, urinary incontinence, urinary retention, urinary tract infection

Reproductive system and breast disorders: amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, impotence, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage

Respiratory, thoracic, and mediastinal disorders: apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, dyspnea exertional, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal congestion, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, pneumonia, pneumonia aspiration, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, rhinitis allergic, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing

Skin and subcutaneous tissue disorders: acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin disorders, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria

Vascular disorders: aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein

   Postmarketing Experience

The following adverse reactions have been identified during post-approval use of immediate-release pramipexole tablets, primarily in Parkinson’s disease patients. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of events were grouped into a smaller number of standardized categories using the MedDRA terminology: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, cardiac failure, compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus, syncope, vomiting, and weight increase.

In a pharmacoepidemiological study, pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole.

7   DRUG INTERACTIONS

No drug interaction studies were conducted with Mirapex ER tablets since the potential for drug interactions mainly depends on the active drug substance pramipexole and not the formulation. Data are available for the immediate-release pramipexole tablet formulation [see Clinical Pharmacology (12.3)].

   Dopamine Antagonists

Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Mirapex ER tablets.

   Drug/Laboratory Test Interactions

There are no known interactions between pramipexole and laboratory tests.

8   USE IN SPECIFIC POPULATIONS

   Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Mirapex ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the maximum recommended human dose (MRHD) on a mg/m2 basis]. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated.  There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.

   Nursing Mothers

A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than in plasma at equivalent time points.

Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

   Pediatric Use

The pharmacokinetics, safety, and efficacy of Mirapex ER tablets in pediatric patients have not been evaluated.

   Geriatric Use

Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of Mirapex ER tablets in early Parkinson’s disease, 47% of the 259 patients were ≥65 years of age. Among patients receiving Mirapex ER tablets, hallucinations were more common in the elderly, occurring in 13% of the patients ≥65 years of age compared to 2% of the patients <65 years of age.

   Patients with Renal Impairment

The elimination of pramipexole is dependent upon renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].

9   DRUG ABUSE AND DEPENDENCE

   Controlled Substance

Pramipexole is not a controlled substance.

   Abuse and Dependence

Pramipexole has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, in a rat model of cocaine self-administration, pramipexole had little or no effect.

10   OVERDOSAGE

There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable, although pulse rate increased to between 100 and 120 beats/minute. No other adverse events were reported related to the increased dose.

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

11   DESCRIPTION

Mirapex ER tablets contain pramipexole, a non-ergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C10 H17 N3 S • 2HCl • H2O, and its molecular weight is 302.26.

The structural formula is:

Pramipexole dihydrochloride is a white to off-white powder substance. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

Mirapex ER tablets, for oral administration, contain 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients are hypromellose, corn starch, carbomer homopolymer, colloidal silicon dioxide, and magnesium stearate.

12   CLINICAL PHARMACOLOGY

   Mechanism of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.  The relevance of D3 receptor binding in Parkinson’s di