natgillin/translations-raw huggingface dataset:
Cobimetinibs farmakokinetik blev evalueret hos 6 forsøgspersoner med let nedsat leverfunktion (Child Pugh A), 6 forsøgspersoner med moderat nedsat leverfunktion (Child Pugh B), 6 forsøgspersoner med svært nedsat leverfunktion (Child Pugh C) og 10 raske forsøgspersoner.
The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment (Child Pugh A), 6 subjects with moderate hepatic impairment (Child Pugh B), 6 subjects with severe hepatic impairment (Child Pugh C) and 10 healthy subjects.
Behandling med Cotellic i kombination med vemurafenib bør udelukkende initieres og superviseres af en kvalificeret læge, der har erfaring med onkologiske lægemidler.
Treatment with Cotellic in combination with vemurafenib should only be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.
Meget sjælden < 1/10.000
Very rare < 1/10,000
Der er ikke gennemført kliniske interaktionsstudier for at vurdere dette fund, og klinisk relevant hæmning af intestinal BCRP kan derfor ikke udelukkes.
No clinical DDI studies have been conducted to assess this finding, and clinically relevant inhibition of intestinal BCRP cannot be ruled out.
Dehydrering, hypofosfatæmi, hyponatriæmi, hyperglykæmi
Dehydration, Hypophosphataemia, Hyponatremia, Hyperglycaemia
Der er kun ganske få data vedrørende Cotellic til patienter med svært nedsat nyrefunktion, og derfor kan en påvirkning ikke udelukkes.
There are minimal data for Cotellic in patients with severe renal impairment, therefore an effect cannot be excluded.
Grad 3 bivirkninger: Cotellic-behandling skal afbrydes under evaluering for at undgå yderligere medvirken til bivirkningen.
Grade 3 events: Cotellic treatment should be interrupted during evaluation to avoid any potential contribution to the event.
Et klinisk interaktionsstudie med kræftpatienter har vist, at plasmakoncentrationen af midazolam (et følsomt CYP3A-substrat) og dextromethorphan (et følsomt CYP2D6-substrat) ikke ændredes ved tilstedeværelse af cobimetinib.
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A substrate) and dextromethorphan (a sensitive CYP2D6 substrate) were not altered in the presence of cobimetinib.
Det Europæiske Lægemiddelagentur har udsat forpligtelsen til at fremlægge resultaterne af studier med Cotellic i en eller flere undergrupper af den pædiatriske population med maligne, solide tumorer (se pkt.
The European Medicines Agency has deferred the obligation to submit the results of studies with Cotellic in one or more subsets of the paediatric population in malignant solid tumours (see section 4.2 for information on paediatric use).
I fase III-studiet med Cotellic i kombination med vemurafenib hos patienter med ikke-operabelt eller metastatisk melanom (n=247) var 183 patienter (74%) < 65 år, 44 patienter (18%) var 65-74 år, 16 patienter (6%) var 75-84 år, og 4 patienter (2%) var ≥ 85 år.
In the Phase III study with Cotellic in combination with vemurafenib in patients with unresectable or metastatic melanoma (n=247), 183 patients (74%) were <65 years of age, and 44 patients (18%) were 65-74 years of age, 16 (6%) were 75-84 years of age, and 4 patients (2%) were aged ³85 years.
Patienter med baseline-LVEF under den nedre grænseværdi eller under 50% af forventet er ikke undersøgt.
Patients with a baseline LVEF either below institutional lower limit of normal (LLN) or below 50% have not been studied.
Det kan ikke udelukkes, at amning er forbundet med en risiko for den nyfødte/barnet.
A risk to the newborns/infants cannot be excluded.
In vitro er cobimetinib en moderat hæmmer af BCRP (Breast Cancer Resistance Protein).
In vitro, cobimetinib is a moderate inhibitor of BCRP (Breast Cancer Resistance Protein).
Hvide, runde, filmovertrukne tabletter, ca. 6,6 mm i diameter med “COB” præget på den ene side.
White, round film-coated tablets of approximately 6.6 mm diameter, with “COB” debossed on one side.
Efter intravenøs administration af 2 mg cobimetinib var den gennemsnitlige plasma-clearance 10,7 l/t.
Following intravenous administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL) was 10.7 L/hr.
Baseret på prækliniske data og den humane massebalance-undersøgelse metaboliseres cobimetinib med minimal renal elimination.
Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, with minimal renal elimination.
Andre lægemidler med ingen eller minimal CYP3A-induktion bør i stedet overvejes.
Alternative agents with no or minimal CYP3A induction should be considered.
En farmakokinetisk populationsanalyse med data fra 151 patienter med let nedsat nyrefunktion (kreatinin-clearance (CRCL) 60 til < 90 ml/min), 48 patienter med moderat nedsat nyrefunktion (CRCL 30 til < 60 ml/min) og 286 patienter med normal nyrefunktion (CRCL ≥ 90 ml/min) viste, at CRCL ikke påvirkede eksponeringen af cobimetinib i signifikant grad.
A population pharmacokinetic analysis using data from 151 patients with mild renal impairment (creatinine clearance (CRCL) 60 to less than 90 mL/min), 48 patients with moderate renal impairment (CRCL 30 to less than 60 mL/min), and 286 patients with normal renal function (CRCL greater than or equal to 90 mL/min), showed that CRCL had no meaningful influence on exposure of cobimetinib.
Tabletterne indeholder lactose (en sukkerart).
The tablets contain lactose (a type of sugar).
Rabdomyolyse er blevet observeret efter markedsføring.
Rhabdomyolysis has been reported in the post-marketing setting.
Tag Cotellic igen næste dag, helt som du plejer.
Continue to take Cotellic as normal, the next day.
Hvis noget af ovenstående gælder for dig (eller hvis du er usikker), skal du tale med lægen, apotekspersonalet eller sygeplejersken, inden du tager Cotellic.
If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before taking Cotellic.
Cobimetinibs farmakokinetik er lineær i dosisområdet ~3,5 mg til 100 mg.
Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg.
Det frarådes at bruge Cotellic til børn og unge.
Cotellic is not recommended for children and adolescents.
Kontakt lægen, apotekspersonalet eller sundhedspersonalet, før du tager Cotellic, hvis du har problemer med: · blødning eller tager medicin, der kan forårsage blødning · øjnene · hjertet · leveren · muskler
Talk to your doctor, pharmacist or nurse before taking Cotellic if you have: · bleeding or are taking any medications that may cause bleeding · an eye problem · heart problems · liver problems · muscle problems.
Vejledning i dosisændringer ved nedsat funktion af venstre ventrikel Permanent seponering af Cotellic-behandling bør overvejes, hvis hjertesymptomerne tilskrives Cotellic og ikke forbedres efter midlertidig behandlingsafbrydelse.
Dose modification advice for left ventricular dysfunction Permanent discontinuation of Cotellic treatment should be considered if cardiac symptoms are attributed to Cotellic and do not improve after temporary interruption.
Det skal du vide, før du begynder at tage Cotellic Tag ikke Cotellic: · hvis du er allergisk over for cobimetinib eller et af de øvrige indholdsstoffer i medicinen
What you need to know before you take Cotellic Do not take Cotellic: · if you are allergic to cobimetinib or any of the other ingredients of this medicine (listed in section 6).
· Hvis du får bivirkninger, kan lægen beslutte at nedsætte dosis eller afbryde behandlingen midlertidigt eller permanent.
· If you get side effects, your doctor may decide to lower your dose, stop treatment temporarily or permanently.
CYP3A- og CYP2D6-substrater
CYP3A and CYP2D6 substrates
*Bivirkningsintensitet gradueret efter CTC-AE (Common Terminology Criteria for Adverse Events v4.0)
Consider permanent discontinuation *The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
Cobimetinibs virkning på lægemiddeltransport-systemer
Effects of cobimetinib on drug transport systems
Cotellic kan forårsage svær blødning, især i hjernen eller maven (se også ”Svær blødning” i afsnit 4).
Cotellic can cause severe bleeding, especially in your brain or stomach (see also “Severe bleeding” in Section 4).
Cotellic påvirker i mindre grad evnen til at føre motorkøretøj og betjene maskiner.
Cotellic has minor influence on the ability to drive or use machines.
Mediantiden til debut af bivirkningen var 4 måneder (1-13 måneder).
Median time to initial onset of events was 4 months (1-13 months).
I tabel 4 angives hyppighed af målte abnorme leverværdier og forhøjet kreatinkinase af alle grader samt grad 3-4.
Table 4 provides the frequency of measured liver laboratory abnormalities and elevated creatine phosphokinase for all Grades and Grades 3-4.
Der bør udvises forsigtighed hos patienter med flere risikofaktorer for blødning såsom hjernemetastaser, og/eller hos patienter, der samtidig tager medicin, som øger risikoen for blødning (inkluderer antitrombotisk og antikoagulerende behandling).For håndtering af blødning se pkt.
Caution should be used in patients with additional risk factors for bleeding, such as brain metastases, and/or in patients that use concomitant medications that increase the risk of bleeding (including antiplatelet or anticoagulant therapy).
Det vides ikke, om cobimetinib udskilles i human mælk.
It is not known whether cobimetinib is excreted in human breast milk.
Hvis nye eller forværrede synsforstyrrelser identificeres, anbefales en oftalmologisk undersøgelse.
If symptoms of new or worsening visual disturbances are identified, an ophthalmologic examination is recommended.
Der findes ingen data om sikkerheden og virkningen af Cotellic i kombination med vemurafenib hos patienter med metastaser i centralnervesystemet eller hos patienter med ikke-kutant malignt melanom.
There are no data on the safety or efficacy of Cotellic in combination with vemurafenib in patients with central nervous system metastasis or in patients with non-cutaneous malignant melanoma.
Cotellics sikkerhed og virkning hos børn og unge i alderen < 18 år er ikke klarlagt.
The safety and efficacy of Cotellic in children and adolescents below 18 years of age have not been established.
Svær blødning (almindelige: kan optræde hos op til 1 ud af 10 patienter) Cotellic kan give svær blødning, især i din hjerne eller mave.
Severe bleeding (common: may affect up to 1 in 10 people) Cotellic can cause severe bleeding, especially in your brain or stomach.
Cotellic kan medføre forhøjede niveauer af nogle leverenzymer i blodet under behandlingen.
Cotellic can increase the amount of some liver enzymes in your blood during treatment.
Risikoen for blødninger øges muligvis ved samtidig brug af antitrombotisk og antikoagulerende behandling.
The risk of haemorrhage may be increased with concomitant use of antiplatelet or anticoagulant therapy.
Se produktresuméet for vemurafenib for fuldstændig beskrivelse af alle bivirkninger, som er forbundet med vemurafenib-behandling.
Please refer to the vemurafenib SmPC for complete descriptions of all undesirable effects associated with vemurafenib treatment.
Cobimetinib blev i høj grad metaboliseret og elimineret via fæces.
Cobimetinib was extensively metabolised and eliminated in faeces.
Figur 2 Forest-plot for hazard ratioer for den endelige samlede overlevelse, subgruppeanalyser- intent-to-treat-population (cut-off dato 28. august 2015)
Figure 2: Forest plot for hazard ratios of final overall survival subgroup analyses - Intent to treat population (cut-off date: 28 August 2015)
1 års (75%) og 2 års (48%) estimat for den samlede overlevelse for Cotellic plus vemurafenib-armen var højere end estimatet for placebo plus vemurafenib-armen (henholdsvis 64% og 38%).
The 1-year (75 %) and 2-year (48 %) OS estimates for the Cotellic plus vemurafenib arm were greater than those for placebo plus vemurafenib arm (64 % and 38 % respectively).
LÆGEMIDDELFORM OG INDHOLD (PAKNINGSSTØRRELSE) 63 filmovertrukne tabletter
PHARMACEUTICAL FORM AND CONTENTS 63 film-coated tablets
Hazard ratio (95% konfidensinterval)b
Hazard ratio (95% CI) b
In vitro-studier viser, at cobimetinib ikke er substrat for de hepatiske transportproteiner OATP1B1, OATP1B3 og OCT1, men at det i let grad hæmmer disse transportproteiner.
In vitro studies show that cobimetinib is not a substrate of the liver uptake transporters OATP1B1, OATP1B3 and OCT1, however, it weakly inhibits these transporters.
Cobimetinibs virkning på andre lægemidler
Effects of cobimetinib on other medicinal products
Tabel 4 Leverfunktionsværdier samt andre blodprøveværdier observeret i fase III-studiet GO28141
Table 4 Liver function and other laboratory tests observed in the Phase III Study GO28141
Da koncentrationen af cobimetinib sandsynligvis vil være betydeligt reduceret ved samtidig administration af potente CYP3A-inducerer, kan patientens effekt være kompromitteret.
Given that cobimetinib concentrations are likely to be significantly reduced when co-administered with moderate to strong CYP3A inducers, patient's efficacy may be compromised.
De hyppigste bivirkninger (>20%), som blev observeret ned højere frekvens i placebo-plusvemurafenib-armen, var artralgi, alopeci og hyperkeratose.
The most common adverse reactions (>20%) observed with a higher frequency in the placebo plus vemurafenib arm were arthralgia, alopecia, and hyperkeratosis.
Tabel 2 Vejledning i dosisændring for Cotellic hos patienter med fald i venstre ventrikels uddrivningsfraktion (LVEF) i forhold til baseline
Table 2 Recommended dose modifications for Cotellic in patients with left ventricular ejection fraction (LVEF) decrease from baseline
Den mediane responsvarighed var 14,3 måneder.
The median duration of response was 14.3 months.
Hvis du kaster op, efter du har taget Cotellic, skal du ikke tage en ny dosis Cotellic samme dag.
If you are sick (vomit) after taking Cotellic, do not take an extra dose of Cotellic on that day.
· Øvrige indholdsstoffer: · lactosemonohydrat, mikrokrystallinsk cellulose, croscarmellosenatrium og magnesiumstearat i tabletkernen og · polyvinylalkohol, titandioxid, macrogol og talcum i filmovertrækket.
· The other ingredients are: · lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in the tablet core; and · polyvinyl alcohol, titanium dioxide, macrogol and talc in the film-coating.
· Diarré
· Diarrhoea
Primære baseline-karakteristika: 58% af patienterne var mænd, medianalderen var 55 år (23-88 år), 60% havde metastatisk melanom stadie M1c, og andelen af patienter med forhøjet LDH var 46,3% i Cobimetinib-plus-vemurafenib-armen og 43,0% i placebo-plus-vemurafenib-armen.
Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23 to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated LDH was 46.3% in the cobimetinib plus vemurafenib arm and 43.0% in the placebo plus vemurafenib arm.
Ved administration til drægtige rotter har cobimetinib forårsaget embryoletalitet og føtale misdannelser af de store kar og kraniet ved systemiske eksponeringer svarende til den humane eksponering ved anbefalede doser.
When administered to pregnant rats, cobimetinib caused embryolethality and foetal malformations of the great vessels and skull at systemic exposures similar to human exposure at recommended dose.
Den endelige analyse for den samlede overlevelse for studie GO28141 var udført med data cut off dato 28. august 2015.
The final OS analysis for Study GO28141 was conducted with a data-cut off date of 28 August 2015.
Sådan tages medicinen: · Synk tabletten hel med vand.
Taking the medicine · Swallow the tablets whole with water.
I dette studie blev 129 patienter behandlet med Cotellic og vemurafenib: 63 havde ikke tidligere fået BRAF-hæmmerbehandling, og 66 patienter havde tidligere oplevet progression under behandling med vemurafenib.
This study treated 129 patients with Cotellic and vemurafenib: 63 were BRAF inhibitor (BRAFi) therapy naïve and 66 patients had previously progressed on prior vemurafenib therapy.
Nogle af disse øjenproblemer kan skyldes ophobning af væske under nethinden i øjet (serøs retinopati).
Some of these eye problems may be a result of “serous retinopathy” (a build-up of fluid under the retina in the eye).
Asymptomatisk
Asymptomatic
Samtidig administration af cobimetinib og en potent CYP3A-inducer er ikke undersøgt i kliniske studier, men det er sandsynligt, at eksponeringen af cobimetinib vil falde.
Co-administration of cobimetinib with a strong CYP3A inducer was not assessed in a clinical study, however, a reduction in cobimetinib exposure is likely.
Sikkerhedsprofilen i studie NO25395 svarede til den, der sås i studie GO28141.
The safety profile of Study NO25395 was consistent with that observed in Study GO28141.
Dosis af vemurafenib kan reduceres, hvis dette er klinisk hensigtsmæssigt.
The dose of vemurafenib may be reduced as clinically appropriate.
· Det vides ikke, om Cotellic udskilles i mælken hos mennesker.
· It is not known if Cotellic passes into breast milk.
Det skal besluttes, om amning eller behandling med Cotellic skal ophøre, idet der tages højde for fordelene ved amning for barnet i forhold til de terapeutiske fordele for moderen.
A decision should be made whether to discontinue breast-feeding or discontinue Cotellic therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Hvis du får bivirkninger, kan lægen beslutte at nedsætte dosis eller afbryde behandlingen midlertidigt eller permanent.
If you get side effects your doctor may decide to lower your dose, stop treatment temporarily or permanently.
Antallet af patienter, som oplevede bivirkninger, var sammenligneligt mellem patienter < 65 år og patienter ≥ 65 år.
The proportion of patients experiencing adverse events (AE) was similar in the patients aged <65 years and those aged ³65 years.
Forhøjet blod-kreatinfosfokinase
Blood creatine phosphokinase increase
Cotellics virkning blev evalueret i fase Ib-studiet, NO25395, som var designet til at vurdere sikkerheden, tolerabiliteten, farmakokinetikken og virkningen af Cotellic som tillæg til vemurafenib til behandling af patienter med BRAF-V600-mutationspositiv (verificeret ved cobas® 4800 BRAF-V600
The efficacy of Cotellic was evaluated in Phase Ib Study, NO25395, which was designed to assess the safety, tolerability, pharmacokinetics and efficacy of Cotellic when added to vemurafenib for the treatment of patients with BRAFV600 mutation-positive (as detected by the cobas® 4800 BRAF V600
Cobimetinib blokerer dermed celleproliferationen, der induceres af MAPK-signalvejen ved at hæmme MEK1/2-signalknuden.
Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node.
Det er ikke udført kliniske interaktionsstudier for at vurdere den kliniske betydning af dette fund.
No clinical DDI studies have been conducted to assess the clinical relevance of this finding.
Dette kan være et tegn på muskelbeskadigelse (rabdomyolyse) (se også ”Muskelproblemer” i afsnit 4).
This can be a sign of muscle damage (rhabdomyolysis) (see also “Muscle problems” in Section 4).
Cotellic dosering kan fortsættes uden ændringer.
Cotellic dosing can be continued without modification.
Generelle dosisændringer
General dose modifications
Andre lægemidlers virkning på cobimetinib
Effects of other medicinal products on cobimetinib
Cotellic skal anvendes med forsigtighed til patienter med svært nedsat nyrefunktion.
Cotellic should be used with caution in patients with severe renal impairment.
Patienter med svært nedsat leverfunktion kan have forhøjet plasmakoncentration af frit cobimetinib sammenlignet med patienter med normal leverfunktion (se pkt.
Patients with severe hepatic impairment may have increased plasma concentrations of unbound cobimetinib compared to patients with normal hepatic function (see section 5.2).
Der er ikke gennemført fertilitetsstudier hos dyr, men der er set negative virkninger i forhold til hunners kønsorganer (se pkt.
In animals, no fertility studies have been performed, but adverse effects were seen on reproductive organs (see section 5.3).
Lysoverfølsomhed
Photosensitivity
Rækkefølgen af behandlinger efter progredigering under BRAF-inhibitor-behandling er ikke etableret.
The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.
Tabel 3 Bivirkninger hos patienter behandlet med Cotellic i kombination med vemurafenib i studiet GO28141
Table 3 Adverse drug reactions in patients treated with Cotellic in combination with vemurafenib in Study GO28141^
Forhøjet GGT
Increased GGT
Der er ikke gennemført karcinogenicitetsstudier med cobimetinib.
Carcinogenicity studies have not been conducted with cobimetinib.
In vitro forårsagede cobimetinib en moderat hæmning af hERG-ionkanalen ved koncentrationer (IC50꞊ 0,5 µM [266 ng/ml]), som er ca. 18 gange højere end de maksimale plasmakoncentrationer (Cmax) ved den anbefalede 60 mg dosis (ubundet Cmax꞊14 ng/ml [0,03 µM]).
In vitro, cobimetinib produced moderate hERG ion channel inhibition (IC50= 0.5 µM [266 ng/mL]), which is approximately 18 fold higher than peak plasma concentrations (Cmax) at the 60 mg to be marketed dose (unbound Cmax=14 ng/mL [0.03 µM]).
Mediantiden til debut af serøs retinopati var 1 måned (0-9 måneder).
Median time to initial onset of serous retinopathy events was 1 month (range 0-9 months).
Forhøjet blodkreatinkinase, forhøjet ALAT, forhøjet ASAT, forhøjet gammaglutamyltransferase (GGT), forhøjet blodALP
Blood CPK increased, ALT increased, AST increased, GammaGlutamyltransferase (GGT) increased, Blood ALP increased
nefadozon for depression amiodaron for uregelmæssig hjerterytme diltiazem, verapamil for højt blodtryk imatinib for kræft carbamazepin, phenytoin for kramper perikon naturmedicin for depression.
nefadozone for depression amiodarone for an uneven heartbeat diltiazem, verapamil for high blood pressure imatinib for cancer carbamazepine, phenytoin for fits (seizures)
Øjenproblemer (syn) (meget almindelige: kan optræde hos flere end 1 ud af 10 patienter) Cotellic kan give øjenproblemer.
Eye (vision) problems (very common: may affect more than 1 in 10 people) Cotellic can cause eye problems.
Medicinens formål itraconazol, clarithromycin, erythromycin, telithromycin, voriconazol, rifampicin, posaconazol, fluconazol, miconazol for bestemte svampe- og bakterieinfektioner ritonavir, cobicistat, lopinavir, delavirdin, amprenavir, fosamprenavir for HIV-infektion telaprevir for hepatitis C
Purpose of the medicine itraconazole, clarithromycin, erythromycin, telithromycin, voriconazole, rifampicin, posaconazole, fluconazole, miconazole for some fungal and bacterial infections ritonavir, cobicistat, lopinavir, delavirdine, amprenavir, fosamprenavir for HIV infection telaprevir for hepatitis C
Hvis samtidig administration af potente eller moderate CYP3A-hæmmere ikke kan undgås, skal patienterne kontrolleres omhyggeligt for bivirkninger, og dosis skal ændres, hvis dette er klinisk indiceret (se tabel 1 i pkt.
If concomitant use with a strong or moderate CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety and dose modifications applied if clinically indicated (see Table 1 in section 4.2).
Patienten skal vurderes for nye eller forværrede synsforstyrrelser ved hvert besøg.
Patients should be assessed at each visit for symptoms of new or worsening visual disturbances.
· Hjerteproblemer
· Heart problems
Mediantiden, der går ind til første forekomst af grad 3 eller 4 stigninger i kreatinkinase var 16 dage (spænder fra: 11 dage til 10 måneder); mediantiden, der går før bivirkningen er helt væk var 16 dage (spænder fra: 2 dage til 15 måneder).
The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 11 days to 10 months); the median time to complete resolution was 16 days (range: 2 days to 15 months).
Cobimetinib er substrat for P-glykoprotein (P-gp).
Cobimetinib is a substrate of P-glycoprotein (P-gp).
· Start næste behandlingsperiode (21 dage) med Cotellic efter 7 dages pausen.
· Start your next Cotellic 21 day treatment period after the 7 day break.