Simvastatina Merck may be available in the countries listed below.
Simvastatin is reported as an ingredient of Simvastatina Merck in the following countries:
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ZYPADHERA may be available in the countries listed below.
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Olanzapine pamoate (a derivative of Olanzapine) is reported as an ingredient of ZYPADHERA in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Siesta may be available in the countries listed below.
Bromazepam is reported as an ingredient of Siesta in the following countries:
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Trixilan may be available in the countries listed below.
Cefatrizine comp. with propylene glycole (a derivative of Cefatrizine) is reported as an ingredient of Trixilan in the following countries:
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Regonol is a brand name of pyridostigmine, approved by the FDA in the following formulation(s):
No. There is currently no therapeutically equivalent version of Regonol available.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Regonol. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
There are no current U.S. patents associated with Regonol.
Treating infections caused by certain bacteria. It is also used to treat certain types of acne and used along with other medicines to treat amoeba infections. It may also be used for other conditions as determined by your doctor.
Sumycin Suspension is a tetracycline antibiotic. Tetracyclines slow the growth of sensitive bacteria by interfering with the production of proteins needed by the bacteria to grow. Slowing the bacteria's growth allows the body's defense mechanisms (eg, white blood cells) to destroy them.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Sumycin Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Sumycin Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Sumycin Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Sumycin Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Sumycin Suspension.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Black hairy tongue; bulky loose stools; diarrhea; difficulty swallowing; headache; hoarseness; indigestion; inflammation of the mouth; inflammation of the skin; inflammation or redness of tongue; joint pain; loss of appetite; mouth sores; nausea; sensitivity to sunlight; swelling and itching of the rectum; vomiting.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision; bulging soft spot in the head of infants; increased pressure in the head; prolonged or severe diarrhea; prolonged or severe headache; purple patches under the skin; second infection (fever, chills, sore throat); severe skin reaction to the sun; stomach pain; vaginal irritation or discharge.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Sumycin side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store Sumycin Suspension at room temperature, between 68 and 77 degrees F (20 and 25 degrees C), in a tightly closed container. Protect from heat, moisture, and light. Do not store in the bathroom. Keep Sumycin Suspension out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Sumycin Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Cholinfall may be available in the countries listed below.
Metixene hydrochloride (a derivative of Metixene) is reported as an ingredient of Cholinfall in the following countries:
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Rec.INN
N03AX03
0000061-56-3
C10-H14-N2-O4-S2
290
Antiepileptic agent
Benzenesulfonamide, 4-(tetrahydro-2H-1,2-thiazin-2-yl)-, S,S-dioxide
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Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Motivan may be available in the countries listed below.
Paroxetine hydrochloride (a derivative of Paroxetine) is reported as an ingredient of Motivan in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
In the US, Chloromycetin (chloramphenicol ophthalmic) is a member of the drug class miscellaneous antibiotics and is used to treat Anthrax, Bacterial Infection, Brucellosis, Cholera, Glanders, Meningitis, Ornithosis, Plague, Psittacosis, Rabbit Fever and Rickettsial Infection.
US matches:
UK matches:
Chloramphenicol is reported as an ingredient of Chloromycetin in the following countries:
Chloramphenicol palmitate (a derivative of Chloramphenicol) is reported as an ingredient of Chloromycetin in the following countries:
Chloramphenicol succinate sodium (a derivative of Chloramphenicol) is reported as an ingredient of Chloromycetin in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Famotidine Healthypharm may be available in the countries listed below.
Cimetidine is reported as an ingredient of Famotidine Healthypharm in the following countries:
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Simvacop may be available in the countries listed below.
Simvastatin is reported as an ingredient of Simvacop in the following countries:
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Synacthène Retard may be available in the countries listed below.
Tetracosactide is reported as an ingredient of Synacthène Retard in the following countries:
Tetracosactide zinc (a derivative of Tetracosactide) is reported as an ingredient of Synacthène Retard in the following countries:
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Bupicaina may be available in the countries listed below.
Bupivacaine hydrochloride (a derivative of Bupivacaine) is reported as an ingredient of Bupicaina in the following countries:
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Gensulin M30 (30/70) may be available in the countries listed below.
Insulin Injection, Biphasic Isophane human (a derivative of Insulin Injection, Biphasic Isophane) is reported as an ingredient of Gensulin M30 (30/70) in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Lincomycin hydrochloride monohydrate (a derivative of Lincomycin) is reported as an ingredient of Spectogard in the following countries:
Spectinomycin dihydrochloride (a derivative of Spectinomycin) is reported as an ingredient of Spectogard in the following countries:
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Fluconazolo DOC may be available in the countries listed below.
Fluconazole is reported as an ingredient of Fluconazolo DOC in the following countries:
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Sibutrin may be available in the countries listed below.
Sibutramine hydrochloride monohydrate (a derivative of Sibutramine) is reported as an ingredient of Sibutrin in the following countries:
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Sibutramina La Santé may be available in the countries listed below.
Sibutramine is reported as an ingredient of Sibutramina La Santé in the following countries:
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Penicilina G Sodica Lafedar may be available in the countries listed below.
Benzylpenicillin sodium (a derivative of Benzylpenicillin) is reported as an ingredient of Penicilina G Sodica Lafedar in the following countries:
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Sibutram may be available in the countries listed below.
Sibutramine is reported as an ingredient of Sibutram in the following countries:
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Diklonat P may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Diklonat P in the following countries:
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Osomol may be available in the countries listed below.
Formaldehyde solution 35% (a derivative of Formaldehyde) is reported as an ingredient of Osomol in the following countries:
Guaiacol is reported as an ingredient of Osomol in the following countries:
International Drug Name Search
Class: Antineoplastic Agents
VA Class: AN300
Molecular Formula: C20H22N8O5
CAS Number: 59-05-2
Brands: Rheumatrex, Trexall
Administer only under supervision of qualified clinicians experienced in use of antimetabolite therapy.b c
Deaths reported with use in treatment of malignancy, psoriasis, and rheumatoid arthritis.b c
Use only for treatment of life-threatening neoplastic diseases or severe, recalcitrant, disabling psoriasis or rheumatoid arthritis in patients who have not responded adequately to other forms of therapy.b c
Closely monitor patients for bone marrow, hepatic, pulmonary, or renal toxicities.b c (See Major Toxicities under Cautions.)
Inform patients of risks involved with therapy and importance of remaining under care of clinician throughout therapy.b c
Use of high-dose regimens recommended for treatment of osteosarcoma requires meticulous care.b (See High-Dose Methotrexate Therapy with Leucovorin Rescue and also see Osteosarcoma, under Dosage and Administration.)
Use of high-dose regimens for other neoplastic diseases is investigational; therapeutic advantage not established.b
Do not use formulations or diluents containing preservatives for intrathecal administration or high-dose therapy.b
Fetal death and/or congenital anomalies reported.b c Not recommended for use in women of childbearing potential unless potential benefit clearly outweighs risks; do not use in pregnant women with psoriasis or rheumatoid arthritis.b c (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)
Elimination reduced in patients with renal impairment, ascites, or pleural effusions.b c Carefully monitor for toxicity in such patients; dosage reduction or discontinuance may be required.b c
Unexpectedly severe, sometimes fatal, myelosuppression, aplastic anemia, and GI toxicity reported with concomitant use of methotrexate (usually at high dosages) and some NSAIAs.b c (See Specific Drugs under Interactions.)
Possible hepatotoxicity, fibrosis, and cirrhosis, generally only after prolonged use.b c (See Hepatic Effects under Cautions.)
Acute liver enzyme elevations frequently observed; usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease.b c
Liver biopsy after sustained use often shows histologic changes.b c Fibrosis and cirrhosis may not be preceded by symptoms or abnormal liver function tests in patients with psoriasis; periodic liver biopsies usually recommended in such patients undergoing long-term therapy.b c
Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in patients with rheumatoid arthritis.b c
Potentially dangerous pulmonary lesions, not always reversible, may occur acutely at any time during therapy and have been reported at dosages as low as 7.5 mg weekly.b c Pulmonary symptoms (especially dry, nonproductive cough) may require therapy interruption and careful evaluation.b c
Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.b c
Malignant lymphomas (e.g., non-Hodgkin’s lymphoma) may occur in patients receiving low-dose oral therapy; such lymphomas may regress following methotrexate discontinuance and may not require cytotoxic therapy.a b c If the lymphoma does not regress following discontinuance, institute appropriate therapy.b c
May induce tumor lysis syndrome in patients with rapidly growing tumors; appropriate pharmacologic and supportive treatment may prevent or alleviate syndrome.b c
Severe, occasionally fatal skin reactions reported following single or multiple doses; reactions occurred within days of oral, IM, IV, or intrathecal administration.b c Recovery reported with discontinuance of therapy.b c (See Dermatologic and Sensitivity Reactions under Cautions.)
Potentially fatal opportunistic infections, especially Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia.b c
Possible increased risk of soft tissue necrosis and osteonecrosis in patients receiving methotrexate concomitantly with radiotherapy.b c
Antineoplastic agent and immunosuppressant; folic acid antagonist.a b c
Treatment (alone or, more commonly, in combination chemotherapy) of breast cancer.a b c
First-line adjuvant chemotherapy in combination with other drugs (i.e., cyclophosphamide and fluorouracil, with or without hormonal therapy).166 167 168 169 170 171 172 173 174 175 178 179 182 185 186 187 d An anthracycline-containing regimen is preferred in patients with node-positive disease.d
Some studies suggest a slight advantage for anthracycline-containing regimens in relapse-free and survival rates in both premenopausal and postmenopausal patients.l
Also used in patients with metastatic disease.d l
Palliative treatment (alone and in combination therapy) of recurrent or metastatic head and neck carcinoma.182 210 211 212 b c d
Frequently used in combination regimens with other antineoplastic agents (e.g., bleomycin, fluorouracil, vincristine).210
Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for recurrent or metastatic squamous cell carcinoma of the head and neck.212
Further study needed to establish comparative benefit of methotrexate-containing regimens.210 212
Component of various chemotherapy regimens in palliative treatment of acute leukemias.a b c
Intrathecally for prophylaxis and treatment of meningeal leukemia.a b d
First-line therapy in combination with mercaptopurine for maintenance of drug-induced remissions of acute lymphoblastic leukemia (ALL).b c d
Has been used in high doses as a component of some alternative combination chemotherapy regimens for remission induction in ALL, but not generally considered a drug of choice for remission induction.d
Rarely effective alone for treatment of acute myeloblastic leukemia (AML);a has been used as an additional component in some chemotherapy regimens for induction or post-induction therapy of AML.a d
Has been used in second-line therapy of recurrent small cell lung cancer.235 b c n
Although labeled for use in squamous cell type of non-small cell lung cancer,127 b c other agents are preferred.182 d
Component of combination chemotherapeutic regimens as first-line palliative therapy for high-grade Burkitt’s lymphoma or maintenance therapy for high-grade lymphoblastic non-Hodgkin’s lymphoma.b c d
Component of alternative combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas (diffuse large cell, diffuse small cell, diffuse mixed, follicular large cell).d
Has been used intrathecally in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab for first-line therapy of intermediate-grade non-Hodgkin’s lymphomas.d
Although radiation or topical therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in generalized stages of these diseases.a
First-lined systemic chemotherapy for advanced cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).b c o
First-line line therapy of primary CNS lymphoma.d
Hodgkin’s disease responds poorly to methotrexate.a
High-dose therapy, followed by leucovorin rescue, in combination chemotherapy regimens as adjunct to surgical resection or amputation of primary tumor in patients with nonmetastatic osteosarcomab d h (designated an orphan drug by FDA for this use).192
Also has been used as a component of adjunctive combination chemotherapy regimens in patients with metastatic osteosarcoma.h
Symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy in carefully selected patients; not curative.a b c
Use only after diagnosis definitely established (e.g., biopsy, after dermatologic consultation).b c
Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.111 112 113 114 115 116 127 128 138 139 140 141 142 143 144 145 146 147 148 149 152 153 154 b c
Management of active polyarticular-course juvenile rheumatoid arthritis in children who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy (i.e., full-dose NSAIAs).b c (See Pediatric Use under Cautions.)
One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.220 224
Substantially greater long-term efficacy than other DMARDs; used as the initial or anchor DMARD in many patients with rheumatoid arthritis.220 222 224 225 226 Also has been used in combination with other DMARDs.220 222 225 228 229 230 231 232 233 234
Use only as part of a comprehensive treatment program, including nondrug therapies (e.g., rest, physical therapy).127
No substantial evidence that methotrexate permanently arrests or reverses the underlying disease process,127 128 138 140 144 147 153 although disease progression is slowed in some patients.138 140 143 144 160 220
Treatment (with or without leucovorin) of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, hydatidiform mole) in women (except those with impaired renal or hepatic function or who have failed to respond to previous methotrexate therapy, in which case dactinomycin is used).a b c e
Most effective in patients who have had disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases.a
First-line therapy with or without leucovorin in patients with nonmetastatic or good-prognosis metastatic gestational trophoblastic neoplasms.d e
Component of combination chemotherapy regimen with dactinomycin and chlorambucil in patients with good-prognosis metastatic gestational trophoblastic neoplasms with refractory disease.e
In patients with poor-prognosis metastatic trophoblastic neoplasms, methotrexate in combination with etoposide, dactinomycin, vincristine, and cyclophosphamide (EMA-CO) is a standard treatment option.e A dose-intensive regimen, EMA-CE, in which etoposide and cisplatin are substituted for vincristine and cyclophosphamide of the EMA-CO regimen, may offer additional benefits.e
Has been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.a
Testicular choriocarcinomas are usually resistant to methotrexate alone; has been used as component of combination therapy in patients with metastatic tumors of the testes.a
Used in combination regimens with vinblastine and cisplatin, with or without doxorubicin, as first- or second-line therapyd for invasive and advanced bladder cancer†.182 205 206 207 208 209
Use of leucovorin rescue or deletion of methotrexate is advised if methotrexate-containing regimens are being considered for the treatment of advanced or metastatic bladder cancer in patients with renal dysfunction, edema, pleural fluid collections, or ascites.205
Management of chronically active Crohn’s disease†.241 242 243 244 245 246 247 248 249 250 251 258 259 260
Used as an alternative to surgical management of ectopic pregnancy† in selected patients with small, unruptured tubal pregnancies.i j k
Low-dose oral therapy has been used in patients with chronic progressive multiple sclerosis†.201 202 203 204
Has been used for its immunosuppressive and/or anti-inflammatory effects in treatment of psoriatic arthritis†.109 110
Consult specialized references for procedures for proper handling and disposal of antineoplastics.b c
Do not prescribe or dispense on as-needed (“prn”) basis.c
If toxicity previously necessitated discontinuance, reinstitute with caution; consider further need for drug and risk of toxicity recurrence.a b c
Use of high-dose regimens employed in adjunctive treatment of osteosarcoma requires meticulous understanding of risks associated with therapy and leucovorin rescue.a b
Hydrate patients with 1 L/m2 of IV fluid over 6 hours prior to initiation of methotrexate infusion.b Continue hydration at 125 mL/m2 per hour (3 L/m2 daily) during methotrexate infusion and for 2 days after completion of infusion.b
Alkalinize urine with sodium bicarbonate to maintain pH >7 during methotrexate infusion and leucovorin calcium therapy; administer sodium bicarbonate orally or via a separate IV solution.b
Scr must be normal and Clcr >60 mL/minute before therapy initiation.b Repeat Scr and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate concentration is <0.023 mcg/mL (0.05 mcM).b
Measure Scr prior to each subsequent course of therapy; if Scr increases by ≥50% compared to prior value, measure and document that Clcr >60 mL/minute (even if Scr is still within normal range).b
Also consult manufacturer’s labeling and published protocols for specific recommendations based on laboratory and clinical findings.a
Administer orally or by IM, IV, or intrathecal injection; may also administer intra-arterially.b c Has been administered by sub-Q injection.c p
Do not use formulations or diluents containing preservatives (e.g., benzyl alcohol) for intrathecal administration or high-dose therapy.b
Administer orally as tablets.c
Oral administration is often preferred when low doses are used since absorption is rapid and effective serum concentrations are achieved.b c
Manufacturer makes no specific recommendations regarding administration with meals; food delays absorption and reduces peak serum concentrations.214 b c
Inadvertent daily instead of weekly administration in patients with psoriasis or rheumatoid arthritis may result in fatal toxicity; carefully instruct patient regarding regimen and frequency of administration.c (See Advice to Patients.)
Mnemonic dispensing packages (e.g., Rheumatrex Dose Pack) may be used for initial and maintenance therapy in patients receiving weekly doses of 5–15 mg but are not recommended for titration to weekly doses >15 mg.a c
For solution and drug compatibility information, see Compatibility under Stability.
Administer by IV injection or infusion.b
Reconstitute lyophilized powder for injection immediately before use with a sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).b
Reconstitute 20 mg vial to a concentration ≤25 mg/mL.b Reconstitute 1 g vial with 19.4 mL of appropriate solution to yield a concentration of 50 mg/mL.b
When high doses are administered by IV infusion, dilute total dose of reconstituted solution in 5% dextrose injection.b
May further dilute commercially available solution for IV injection containing preservatives with a compatible solution (e.g., 0.9% sodium chloride injection).b
Preservative-free solutions may be diluted immediately prior to use with an appropriate sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).b
Administer by IM injection.b
Reconstitute lyophilized powder for injection immediately before use with a sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).b
Preservative-free solutions (1 mg/mL) are used for intrathecal injection.b Do not administer solutions containing preservatives intrathecally.b
Must administer intrathecally for treatment of meningeal leukemia since passage of drug from blood to CSF is minimal.a b
Prior to intrathecal administration, a volume of CSF approximately equivalent to volume of solution to be injected (e.g., 5–15 mL) is usually removed.a
If lumbar puncture is traumatic, do not administer intrathecally; allow 2 days to elapse before again attempting injection.a
Inject intrathecally only if there is easy flow of blood-free spinal fluid.a
Some clinicians recommend that entire volume of methotrexate injection be injected intrathecally in 15–30 seconds.a Aspiration should not be performed.a
Appears in systemic circulation following intrathecal administration; adjust, reduce, or discontinue any concomitant systemic administration as appropriate.a b
Systemic administration of leucovorin calcium simultaneously with intrathecal methotrexate may prevent systemic toxicity without abolishing drug’s activity in CNS.a
For intrathecal injection, reconstitute lyophilized powder to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).b
For intrathecal injection, dilute methotrexate preservative-free solution for injection to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).b
Available as methotrexate sodium; dosage is expressed in terms of methotrexate.b c
Various dosage schedules have been used; individualize dosage, route of administration, and duration of therapy according to disease being treated, other therapy employed, and condition, response, and tolerance of the patient.a Consult published protocols for additional information on alternative regimens and dosages.
May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects associated with the drug.c
Initially, 10 mg/m2 once weekly.b c May adjust dosage gradually to achieve optimal response.b c
Dosages up to 30 mg/m2 weekly have been used in children, but published data are too limited to assess risk of serious toxicity at dosages >20 mg/m2 weekly.b c
Children receiving 20–30 mg/m2 (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.b c
Optimum duration of therapy is unknown.b c
Children receiving 20–30 mg/m2 (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.b c
Regardless of method used to determine intrathecal dosage, carefully check dose prior to administration to minimize risk of inadvertent intrathecal overdosage.106
Clinical studies indicate that intrathecal dosage regimens based on age may be more effective and less neurotoxic than dosage regimens based on body surface area.107 108 127 b
Age | Dose |
|---|---|
<1 year | 6 mg |
1 year | 8 mg |
2 years | 10 mg |
≥3 years | 12 mg |
Intrathecal doses based on body surface area (i.e., 12 mg/m2, maximum 15 mg) reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients.b
Treatment: may administer at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable.b Administration at intervals of <1 week may result in increased subacute toxicity.b
Prophylaxis: dosage is the same as for treatment; administration intervals differ from regimen used in treatment.a b Consult specialized references and medical literature for specific recommendations.a b
Various combination chemotherapy regimens have been used in the treatment of breast cancer; consult published protocols for dosages and method and sequence of administration.168 169 170 171 172 173 174 176 180 181 183 185 187
Dose intensity of adjuvant combination chemotherapy appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; avoid arbitrary reductions in dose intensity.166 170 187
Dosage of 40 mg/m2 IV on days 1 and 8 of each cycle in combination with cyclophosphamide 100 mg/m2 on days 1–14 of each cycle and fluorouracil 600 mg/m2 on days 1 and 8 of each cycle is commonly employed for treatment of early breast cancer.168 169 187
In patients >60 years of age, initial dosage is reduced to 30 mg/m2 and initial fluorouracil dosage is reduced to 400 mg/m2; 169 dosage also reduced if myelosuppression develops.168 169
Cycles are generally repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6–12 cycles (i.e., 6–12 months of therapy).168 169 187
In a sequential regimen in which several courses of doxorubicin are administered prior to a regimen of cyclophosphamide, methotrexate, and fluorouracil in patients with early breast cancer and >3 positive axillary lymph nodes,171 4 doses of doxorubicin hydrochloride 75 mg/m2 were administered initially at 3-week intervals followed by 8 cycles of methotrexate 40 mg/m2, cyclophosphamide 600 mg/m2, and fluorouracil 600 mg/m2 at 3-week intervals for a total of approximately 9 months of therapy.171 185 If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than dosage reduced.171 185
Not generally a drug of choice, but 3.3 mg/m2 daily in combination with prednisone 40–60 mg/m2 daily for 4–6 weeks has been used.a b c
After remission attained, 20–30 mg/m2 total weekly dose, administered in divided doses twice weekly.a b c
Alternatively, 2.5 mg/kg has been administered IV every 14 days.a b c
Treatment: 12 mg administered at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable.b However, administration at intervals of <1 week may result in increased subacute toxicity.b
Prophylaxis: 12 mg; administration intervals differ from regimen used in treatment.a b Consult specialized references and medical literature for specific recommendations.a b
Intrathecal doses of 12 mg/m2 (maximum 15 mg) reported to result in high CSF methotrexate concentrations and neurotoxicity in adults.b
For Burkett’s lymphoma (stage I or II), 10–25 mg daily for 4–8 days.b c In stage III Burkitt’s lymphoma, commonly given with other antineoplastic agents.b c In all stages, several courses are usually administered, interposed with 7- to 10-day rest periods.b c
Stage III lymphosarcomas may respond to combined drug therapy with methotrexate given in doses of 0.625–2.5 mg/kg daily.b c
Usually, 5–50 mg weekly in early stages.b c 241 Dose reduction or discontinuance is determined by hematologic monitoring and patient response.c 241
Also has been administered twice weekly in doses ranging from 15–37.5 mg in patients who have responded poorly to weekly therapy.b c 241
Combination chemotherapy regimens that include higher-dose methotrexate with leucovorin rescue have been used in advanced stages.b c 241 Consult published protocols for dosages.
Initially, 12 g/m2 infused over 4 hours on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery on a schedule in combination with other chemotherapy agents (e.g., doxorubicin; cisplatin; combination of bleomycin, cyclophosphamide, and dactinomycin).b If initial dosage is not sufficient to produce peak serum methotrexate concentrations of 454 mcg/mL (1000 mcM [10-3 mol/L]) at the end of IV infusion, may increase dose to 15 g/m2 in subsequent treatments.b
Initiate leucovorin rescue therapy at a dosage of 15 mg orally every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion.b May give leucovorin IV or IM if patient cannot tolerate oral therapy.b If clinically important methotrexate toxicity is observed, extend leucovorin therapy for an additional 24 hours (total of 14 doses instead of 10) in subsequent courses.b
Delay subsequent methotrexate administration until recovery if the following adverse effects occur: if WBC count is <1500/mm3; neutrophil count is <200/mm3; platelet count is <75,000/mm3; serum bilirubin concentration is >1.2 mg/dL; ALT concentration is >450 units; mucositis is present (until there is evidence of healing); or persistent pleural effusion is present (drain dry prior to infusion).b
Clinical Situation | Laboratory Findings | Leucovorin Dosage and Duration |
|---|---|---|
Normal methotrexate elimination | Serum methotrexate concentration approximately 4.54 mcg/mL (10 mcM) at 24 hours after administration, 0.454 mcg/mL (1 mcM) at 48 hours, and <0.091 mcg/mL (0.2 mcM) at 72 hours | 15 mg orally, IM, or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion) |
Delayed late methotrexate elimination | Serum methotrexate concentration remaining >0.091 mcg/mL (0.2 mcM) at 72 hours and >0.023 mcg/mL (0.05 mcM) at 96 hours after administration | Continue 15 mg orally, IM, or IV every 6 hours, until methotrexate concentration is <0.023 mcg/mL (0.05 mcM) |
Delayed early methotrexate elimination and/or evidence of acute renal injury | Serum methotrexate ≥22.7 mcg/mL (50 mcM) at 24 hours or ≥2.27 mcg/mL (5 mcM) at 48 hours after administration, or a ≥100% increase in Scr concentration at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a concentration of ≥1 mg/dL) | 150 mg IV every 3 hours, until methotrexate concentration is <0.454 mcg/mL (1 mcM), then 15 mg IV every 3 hours until methotrexate concentration is <0.023 mcg/mL (0.05 mcM) |
Administration of a single 5- to 10-mg dose 1 week prior to initiation of therapy has been recommended to detect idiosyncratic reactions.a
Divided oral dosage schedule: 2.5 mg at 12-hour intervals for 3 doses each week.c May gradually adjust dosage by 2.5 mg/week to achieve optimal response; do not exceed 30 mg weekly ordinarily.a c
Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.c Use may permit return to conventional topical therapy.c
Weekly single-dosage schedule: 10–25 mg as a single dose once weekly until adequate response achieved.c May gradually adjust dosage to achieve optimal response; do not exceed 30 mg weekly ordinarily.c Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.c
May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects.c
Initially, 7.5 mg once weekly or a course once weekly of 2.5 mg administered at 12-hour intervals for 3 doses.c May gradually adjust dosage to achieve an optimal response.c
At dosages >20 mg weekly, possible increased incidence and severity of serious toxic reactions, especially myelosuppression.c
Optimal duration of therapy is not known; limited data indicate that initial improvement is maintained for at least 2 years with continued therapy.c
Usually, 15–30 mg daily for 5 days.b c A repeat course may be given after a period of ≥1 week, provided all signs of residual toxicity have disappeared; 3–5 courses are usually employed.a b c Clinical assessment before each course is essential.b c
Therapy is usually evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which usually normalizes after third or fourth course; complete resolution of measurable lesions usually occurs 4–6 weeks later.
1 or 2 courses of therapy are usually given after normalization of urinary hCG concentrations is achieved.
25 mg once weekly has been administered for 16 weeks.241 243 244 250 251
12.5–22.5 mg once weekly has been administered for up to 1 year.252
15 mg once weekly has been used.252
50 mg/m2 as a single dose.i May require second dose or surgical intervention if hCG concentration fails to decrease by at least 15% from day 4 to day 7 after methotrexate administration.i
Alternatively, 1 mg/kg (on days 0, 2, 4, and 6) alternating with 0.1 mg/kg of leucovorin IM (on days 1, 3, 5, and 7) has been used.i k
Although there is experience with dosages up to 30 mg/m2 weekly in children, published data are too limited to assess how dosages >20 mg/m2 weekly might affect risk of serious toxicity.b c
Children receiving 20–30 mg/m2 (0.65–1 mg/kg) weekly may have better absorption and fewer GI effects if administered either IM or sub-Q.b c
Do not ordinarily exceed 30 mg weekly.c
Do not ordinarily exceed 20 mg weekly.c
Limited experience suggests substantial increase in incidence and severity of serious toxic reactions, especially bone marrow suppression, at dosages >20 mg weekly.c
Dose reduction and especially careful monitoring for toxicity required.b c
Select dosage with caution since hepatic and renal function and folate stores may be decreased; closely monitor for early signs of toxicity.b c
Dose reduction and especially careful monitoring for toxicit
Setard may be available in the countries listed below.
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Benzylpenicillin potassium (a derivative of Benzylpenicillin) is reported as an ingredient of Solu Pen in the following countries:
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Rec.INN
D01AC09
0061318-90-9
C18-H15-Cl3-N2-S
397
Antifungal agent
1H-Imidazole, 1-[2-[[(4-chlorophenyl)methyl]thio]-2-(2,4-dichlorophenyl)ethyl]-, (±)-
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Glossary
| BAN | British Approved Name |
| BANM | British Approved Name (Modified) |
| DCF | Dénomination Commune Française |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Sopira Citocartin mit Epinephrin may be available in the countries listed below.
Articaine hydrochloride (a derivative of Articaine) is reported as an ingredient of Sopira Citocartin mit Epinephrin in the following countries:
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Phénacaïne may be available in the countries listed below.
Phénacaïne (DCF) is also known as Phenacaine (Prop.INN)
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| DCF | Dénomination Commune Française |
| Prop.INN | Proposed International Nonproprietary Name (World Health Organization) |
Silkis may be available in the countries listed below.
UK matches:
Calcitriol is reported as an ingredient of Silkis in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
SPIRIVA® 18 microgram, inhalation powder, hard capsule
Each capsule contains 22.5 microgram tiotropium bromide monohydrate equivalent to 18 microgram tiotropium.
The delivered dose (the dose that leaves the mouthpiece of the HandiHaler® device) is 10 microgram tiotropium.
Excipient: Lactose monohydrate
For a full list of excipients, see section 6.1.
Inhalation powder, hard capsule.
Light green hard capsules with the product code TI 01 and company logo printed on the capsule.
Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD).
The recommended dosage of tiotropium bromide is inhalation of the contents of one capsule once daily with the HandiHaler device at the same time of day.
The recommended dose should not be exceeded.
Tiotropium bromide capsules must not be swallowed.
Tiotropium bromide should only be inhaled with the HandiHaler device.
Instructions for handling and use:
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Cleaning your HandiHaler
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Blister handling
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SPIRIVA® capsules contain only a small amount of powder so that the capsule is only partially filled.
Special Populations:
Geriatric patients can use tiotropium bromide at the recommended dose.
Renally impaired patients can use tiotropium bromide at the recommended dose. For patients with moderate to severe impairment (creatinine clearance
Hepatically impaired patients can use tiotropium bromide at the recommended dose (see 5.2 Pharmacokinetic properties).
Paediatric patients: Safety and effectiveness of tiotropium bromide inhalation powder in paediatric patients have not been established and therefore it should not be used in patients under 18 years of age.
Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium bromide, atropine or its derivatives, e.g. ipratropium or oxitropium or to the excipient lactose monohydrate which contains milk protein.
Tiotropium bromide, as a once daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy.
Immediate hypersensitivity reactions may occur after administration of tiotropium bromide inhalation powder.
Consistent with its anticholinergic activity, tiotropium bromide should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction. (see 4.8 undesirable effects)
Inhaled medicines may cause inhalation-induced bronchospasm.
As plasma concentration increases with decreased renal function in patients with moderate to severe renal impairment (creatinine clearance
Patients should be cautioned to avoid getting the drug powder into their eyes. They should be advised that this may result in precipitation or worsening of narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema. Should any combination of these eye symptoms develop, patients should stop using tiotropium bromide and consult a specialist immediately.
Dry mouth, which has been observed with anti-cholinergic treatment, may in the long term be associated with dental caries.
Tiotropium bromide should not be used more frequently than once daily (see section 4.9 Overdose).
SPIRIVA capsules contain 5.5 mg lactose monohydrate.
Although no formal drug interaction studies have been performed, tiotropium bromide inhalation powder has been used concomitantly with other drugs without clinical evidence of drug interactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD.
The co-administration of tiotropium bromide with other anticholinergic-containing drugs has not been studied and is therefore not recommended.
For tiotropium bromide, no documented clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity associated with maternal toxicity (see section 5.3, Preclinical Safety Data). The potential risk for humans is unknown. SPIRIVA should therefore only be used during pregnancy when clearly indicated.
It is unknown whether tiotropium bromide is excreted in human breast milk. Despite studies in rodents which have demonstrated that excretion of tiotropium bromide in breast milk occurs only in small amounts, use of SPIRIVA is not recommended during breast-feeding. Tiotropium bromide is a long-acting compound. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with SPIRIVA should be made taking into account the benefit of breast-feeding to the child and the benefit of SPIRIVA therapy to the woman.
No studies on the effects on the ability to drive and use machines have been performed. The occurrence of dizziness, blurred vision, or headache may influence the ability to drive and use machinery.
a) General Description
Many of the listed undesirable effects can be assigned to the anticholinergic properties of SPIRIVA.
b) Table of Undesirable Effects
The frequencies assigned to the undesirable effects listed below are based on crude incidence rates of adverse drug reactions (i.e. events attributed to tiotropium) observed in the tiotropium group (9,149 patients) from 26 pooled placebo-controlled clinical trials with treatment periods ranging from four weeks to four years.
Frequency is defined using the following convention:
Very common (
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*no events attributed to tiotropium in 9,149 tiotropium treated patients; however, events are considered adverse drug reactions associated with tiotropium
c) Information Characterising Individual Serious and/or Frequently Occurring Undesirable Effects
In controlled clinical studies, the commonly observed undesirable effects were anticholinergic undesirable effects such as dry mouth which occurred in approximately 4% of patients. In 26 clinical trials, dry mouth led to discontinuation in 18 of 9,149 tiotropium treated patients (0.2%).
Serious undesirable effects consistent with anticholinergic effects include glaucoma, constipation and intestinal obstruction including ileus paralytic as well as urinary retention.
Additional information on special populations
An increase in anticholinergic effects may occur with increasing age.
High doses of tiotropium bromide may lead to anticholinergic signs and symptoms.
However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 340 microgram tiotropium bromide in healthy volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were observed following 7 day dosing of up to 170 microgram tiotropium bromide in healthy volunteers. In a multiple dose study in COPD patients with a maximum daily dose of 43 microgram tiotropium bromide over four weeks no significant undesirable effects have been observed.
Acute intoxication by inadvertent oral ingestion of tiotropium bromide capsules is unlikely due to low oral bioavailability.
Pharmacotherapeutic group: Anticholinergics
ATC code: R03B B04
Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, tiotropium bromide competitively and reversibly antagonises the M3 receptors, resulting in relaxation. The effect was dose dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M3 receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur. The bronchodilation is primarily a local effect (on the airways), not a systemic one.
Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M3 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
Electrophysiology: In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.
The clinical development programme included four one-year and two six-month randomised, double-blind studies in 2663 patients (1308 receiving tiotropium bromide). The one-year programme consisted of two placebo-controlled trials and two trials with an active control (ipratropium). The two six-month trials were both, salmeterol and placebo controlled. These studies included lung function and health outcome measures of dyspnea, exacerbations and health-related quality of life.
In the aforementioned studies, tiotropium bromide, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second, FEV1 and forced vital capacity, FVC) within 30 minutes following the first dose which was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. Tiotropium bromide significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings. The bronchodilator effects of tiotropium bromide were maintained throughout the one-year period of administration with no evidence of tolerance.
A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether the drug was administered in the morning or in the evening.
The following health outcome effect was demonstrated in the long term (6-month and one-year) trials:
Tiotropium bromide significantly improved dyspnea (as evaluated using the Transition Dyspnea Index.). This improvement was maintained throughout the treatment period.
The impact of improvements in dyspnea on exercise tolerance was investigated in two randomised, double-blind, placebo-controlled trials in 433 patients with moderate to severe COPD. In these trials, six weeks of treatment with SPIRIVA significantly improved symptom-limited exercise endurance time during cycle ergometry at 75% of maximal work capacity by 19.7% (Trial A: 640 seconds with SPIRIVA vs. 535 seconds with placebo, compared with a pre-treatment baseline of 492 seconds) and 28.3% (Trial B: 741 seconds with SPIRIVA vs. 577 seconds with placebo, compared with a pre-treatment baseline of 537 seconds).
In a randomized, double-blind, placebo controlled trial of 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the proportion of patients who experienced exacerbations of COPD (32.2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In addition, 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056). The number of hospitalizations due to COPD was reduced by 30% (0.25 to 0.18 events per patient year of exposure).
In a 9-month, randomized, double-blind, placebo-controlled clinical trial of 492 patients, SPIRIVA improved health-related quality of life as determined by the St. George's Respiratory Questionnaire (SGRQ) total score. The proportion of patients treated with SPIRIVA which achieved a meaningful improvement in the SGRQ total score (i.e.> 4 units) was 10.9% higher compared with placebo (59.1% in the SPIRIVA groups vs. 48.2% in the placebo group (p=0.029). The mean difference between the groups was 4.19 units (p=0.001; confidence interval: 1.69 – 6.68). The improvements of the subdomains of the SGRQ-score were 8.19 units for “symptoms”, 3.91 units for “activity” and 3.61 units for “impact on daily life”. The improvements of all these separate subdomians were statistically significant.
In a 4-year, randomised, double-blind, placebo-controlled clinical trial of 5,993 randomised patients (3,006 receiving placebo and 2,987 receiving Spiriva), the improvement in FEV1 resulting from Spiriva, compared with placebo, remained constant throughout 4 years. A higher proportion of patients completed 1 compared to placebo was similar between Spiriva and placebo. During treatment, there was a 16% reduction in the risk of death. The incidence rate of death was 4.79 per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the tiotropium group (hazard ratio (tiotropium/placebo) = 0.84, 95% CI = 0.73, 0.97). Treatment with tiotropium reduced the risk of respiratory failure (as recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).
a) General Introduction
Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
b) General Characteristics of the Active Substance after Administration of the Medicinal Product
Absorption: Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical structure of the compound (quaternary ammonium compound) and from in-vitro experiments that tiotropium bromide is poorly absorbed from the gastrointestinal tract (10-15%). Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Maximum tiotropium bromide plasma concentrations were observed five minutes after inhalation. Food is not expected to influence the absorption of this quaternary ammonium compound.
Distribution: The drug is bound by 72% to plasma proteins and shows a volume of distribution of 32 L/kg. At steady state, tiotropium bromide plasma levels in COPD patients at peak were 17 – 19 pg/ml when measured 5 minutes after dry powder inhalation of a 18 microgram dose and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 3-4 pg/ml. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium bromide does not penetrate the blood-brain barrier to any relevant extent.
Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. The ester tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on muscarinic receptors. In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (< 20% of dose after intravenous administration) is metabolised by cytochrome P450 (CYP) dependent oxidation and subsequent glutathion conjugation to a variety of Phase II-metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP 2D6 and 3A4 are involved in metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination: The terminal elimination half-life of tiotropium bromide is between 5 and 6 days following inhalation. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers with an interindividual variability of 22%. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation urinary excretion is 14% of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. The renal clearance of tiotropium bromide exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2-3 weeks with no accumulation thereafter.
Linearity / Nonlinearity: Tiotropium bromide demonstrates linear pharmacokinetics in the therapeutic range after both intravenous administration and dry powder inhalation.
c) Characteristics in Patients
Geriatric Patients: As expected for all predominantly renally excreted drugs, advanced age was associated with a decrease of tiotropium bromide renal clearance (326 mL/min in COPD patients < 58 years to 163 mL/min in COPD patients> 70 years) which may be explained by decreased renal function. Tiotropium bromide excretion in urine after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients), however plasma concentrations did not change significantly with advancing age within COPD patients if compared to inter- and intraindividual variability (43% increase in AUC0-4h after dry powder inhalation.
Renally Impaired Patients: In common with all other drugs that undergo predominantly renal excretion, renal impairment was associated with increased plasma drug concentrations and reduced renal drug clearance after both intravenous infusion and dry powder inhalations. Mild renal impairment (CLCR 50-80 ml/min) which is often seen in elderly patients increased tiotropium bromide plasma concentrations slightly (39% increase in AUC0-4h after intravenous infusion). In COPD patients with moderate to severe renal impairment (CLCR < 50 ml/min) the intravenous administration of tiotropium bromide resulted in doubling of the plasma concentrations (82% increase in AUC0-4h), which was confirmed by plasma concentrations after dry powder inhalation.
Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on tiotropium bromide pharmacokinetics. Tiotropium bromide is predominantly cleared by renal elimination (74% in young healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.
Paediatric Patients: See 4.2 Posology and Method of Administration
d) Pharmacokinetic / Pharmacodynamic Relationship(s)
There is no direct relationship between pharmacokinetics and pharmacodynamics.
Many effects observed in conventional studies of safety pharmacology, repeated dose toxicity, and reproductive toxicity could be explained by the anticholinergic properties of tiotropium bromide. Typically in animals reduced food consumption, inhibited body weight gain, dry mouth and nose, reduced lacrimation and salivation, mydriasis and increased heart rate were observed. Other relevant effects noted in repeated dose toxicity studies were: mild irritancy of the respiratory tract in rats and mice evinced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder in rats.
Harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. Tiotropium bromide was not teratogenic in rats or rabbits. The respiratory (irritation) and urogenital (prostatitis) changes and reproductive toxicity were observed at local or systemic exposures more than five-fold the therapeutic exposure. Studies on genotoxicity and carcinogenic potential revealed no special hazard for humans.
Lactose monohydrate (which contains milk protein)
Not applicable
2 years
After first opening of the blister: 9 days
Discard the HandiHaler device 12 months after first use.
Do not store above 25°C
Do not freeze
Aluminium / PVC / Aluminium blister strips containing 10 capsules
The HandiHaler is a single dose inhalation device made from plastic materials (ABS) and stainless steel.
Package sizes and devices supplied:
• Cardboard box containing 30 capsules (3 blister strips)
• Cardboard box containing 60 capsules (6 blister strips)
• Cardboard box containing 90 capsules (9 blister strips)
• Cardboard box containing HandiHaler device
• Cardboard box containing HandiHaler device and 10 capsules (1 blister strip)
• Cardboard box containing HandiHaler device and 30 capsules (3 blister strips)
• Hospital pack: Bundle pack containing 5 cardboard boxes of 30 capsules plus HandiHaler device
• Hospital pack: Bundle pack containing 5 cardboard boxes of 60 capsules
Not all pack sizes may be marketed
No special requirements.
Boehringer Ingelheim International GmbH
Binger Straße 173
D-55216 Ingelheim am Rhein
Germany
PL 14598/0062
09/10/2006
March 2010
POM
